Systems, methods and apparatuses for manufacturing dosage forms

ABSTRACT

Systems, methods and apparatuses for manufacturing dosage forms, and to dosage forms made using such systems, methods and apparatuses are provided. Novel compression, thermal cycle molding, and thermal setting molding modules are disclosed. One or more of such modules may be linked, preferably via novel transfer device, into an overall system for making dosage forms.

FIELD OF THE INVENTION

[0001] This invention relates generally to systems, methods andapparatuses for manufacturing dosage forms, and to dosage forms madeusing such systems, methods and apparatuses.

BACKGROUND OF THE INVENTION

[0002] A variety of dosage forms, such as tablets, capsules and gelcapsare known in the pharmaceutical arts. Tablets generally refer torelatively compressed powders in various shapes. One type of elongated,capsule-shaped tablet is commonly referred to as a “caplet.” Capsulesare typically manufactured using a two piece gelatin shell formed bydipping a steel rod into gelatin so that the gelatin coats the end ofthe rod. The gelatin is hardened into two half-shells and the rodextracted. The hardened half-shells are then filled with a powder andthe two halves joined together to form the capsule. (See generally,HOWARD C. A NSEL ET AL., Pharmaceutical Dosage Forms and Drug DeliverySystems (7th Ed. 1999).)

[0003] Gelatin-coated tablets, commonly known as geltabs and gelcaps,are an improvement on gelatin capsules and typically comprise a tabletcoated with a gelatin shell. Several well known examples of gelcaps areMcNeil Consumer Healthcare's acetaminophen based products sold under thetrade name Tylenol®. U.S. Pat. Nos. 4,820,524; 5,538,125; 5,228,916;5,436,026; 5,679,406; 5,415,868; 5,824,338; 5,089,270; 5,213,738;5,464,631; 5,795,588; 5,511,361; 5,609,010; 5,200,191; 5,459,983;5,146,730; 5,942,034 describe geltabs and gelcaps and methods andapparatuses for making them. Conventional methods for forming gelcapsare generally performed in a batchwise manner using a number of standalone machines operating independently. Such batch processes typicallyinclude the unit operations of granulating, drying, blending, compacting(e.g., in a tablet press), gelatin dipping or enrobing, drying, andprinting.

[0004] Unfortunately, these processes have certain drawbacks. Forexample, because these systems are batch processes, each of the variousapparatuses employed is housed in a separate clean room that must meetFDA standards. This requires a relatively large amount of capital interms of both space and machinery. A process that would increase andstreamline production rates would therefore provide many economicbenefits including a reduction in the size of facilities needed to massproduce pharmaceutical products. Generally, it would be desirable tocreate a continuous operation process, as opposed to a batch process,for formation of gelcaps and other dosage forms.

[0005] Furthermore, gel dipping and drying operations are in generalrelatively time consuming. Thus, a process that simplifies the gelatincoating operation in particular and reduces drying time would also beadvantageous.

[0006] Current equipment for making gelcaps and geltabs is designed toproduce these forms only according to precise specifications of size andshape. A more versatile method and apparatus, which could be used toproduce a variety of dosage forms to deliver pharmaceuticals,nutritionals, and/or confections, would therefore also be advantageous.

[0007] Accordingly, applicants have now discovered that a wide varietyof dosage forms, including compressed tablets, gelcaps, chewabletablets, liquid fill tablets, high potency dosage forms, and the like,some of which in and of themselves are novel, can be made using uniqueoperating modules. Each operating module performs distinct functions,and therefore may be used as a stand alone unit to make certain dosageforms. Alternatively, two or more of the same or different operatingmodules may be linked together to form a continuous process forproducing other dosage forms. In essence, a “mix and match” system forthe production of dosage forms is provided by the present invention.Preferably, the operating modules may be linked together as desired tooperate as a single continuous process.

SUMMARY OF THE INVENTION

[0008] In a first embodiment, the invention provides a method of makingdosage forms, comprising the steps of: a) compressing a powder into acompressed dosage form in a compression module; b) transferring saidcompressed dosage form to a thermal cycle molding module; c) molding aflowable material around said compressed dosage form in said thermalcycle molding module; and d) hardening said flowable material so as toform a coating over said compressed dosage form; wherein steps (a)through (d) are linked together such that essentially no interruptionoccurs between said steps.

[0009] The invention also provides a method of making dosage forms,comprising the steps of: a) compressing a first powder into a compresseddosage form in a first compression module; b) transferring saidcompressed dosage form to a thermal cycle molding module; c) molding aflowable material around said compressed dosage form in said thermalcycle molding module; d) hardening said flowable material so as to forma coating over said compressed dosage form; e) transferring said coatedcompressed dosage form to a second compression module; and f)compressing a second powder around said coated compressed dosage form insaid second compression module to form a compressed, coated, compresseddosage form; wherein steps (a) through (f) are linked together such thatessentially no interruption occurs between said steps.

[0010] The invention further provides a method of making a dosage form,comprising the steps of: a) forming an insert; b) transferring saidinsert to a thermal cycle molding module; c) molding a flowable materialaround said insert in said thermal cycle molding module; and d)hardening said flowable material so as to form a coating over saidinsert; wherein steps (a) through (d) are linked together such thatessentially no interruption occurs between said steps.

[0011] The invention further provides a method of making a dosage form,comprising the steps of: a) forming at least two inserts; b)transferring said inserts to a thermal cycle molding module; c) moldinga flowable material around said inserts in said thermal cycle moldingmodule; and d) hardening said flowable material so as to form a coatingover said inserts to form a dosage form comprising at least two insertssurrounded by a coating; wherein steps (a) through (d) are linkedtogether such that essentially no interruption occurs between saidsteps.

[0012] The invention also provides a method of making dosage forms,comprising the steps of: a) forming an insert; b) transferring saidinsert to a compression module; c) compressing a powder around saidinsert into a compressed dosage form in a compression module; whereinsteps (a) through (c) are linked together such that essentially nointerruption occurs between said steps.

[0013] The invention also provides a linked apparatus for making dosageforms containing a medicant, comprising: a) a compression module havingmeans for forming compressed dosage forms by compressing a powdercontaining said medicant; b) a transfer device having means forcontinuously transferring said compressed dosage forms from saidcompression module to a thermal cycle molding module; and c) a thermalcycle molding module having means for continuously molding a coating offlowable material over said compressed dosage forms.

[0014] The invention further provides an apparatus for making dosageforms containing a medicant, comprising: a) a first rotor comprising aplurality of die cavities disposed around the circumference thereof soas to be carried around a first circular path by said rotor, each ofsaid die cavities having an opening for receiving powder and at leastone punch mounted for displacement into said die cavity, wherebydisplacement of said punch into said die cavity compresses powdercontained in said die cavity into a compressed dosage form; b) a secondrotor comprising a plurality of mold cavities disposed around thecircumference thereof so as to be carried around a second circular pathby said second rotor, each of said mold cavities capable of enclosing atleast a portion of a compressed dosage form and capable of receivingflowable material so as to coat said portion of said compressed dosageform enclosed by said mold cavity; and c) a transfer device fortransferring compressed dosage forms from said first rotor to saidsecond rotor, said transfer device comprising a plurality of transferunits guided around a third path, a first portion of said third pathbeing coincident with said first circular path and a second portion ofsaid third path being coincident with said second circular path.

[0015] The invention also provides a method of forming compressed dosageforms, comprising: a) placing a supply of powder in flow communicationwith a die, said die comprising a die cavity therein in flowcommunication with a filter; b) applying suction to said die cavity soas to cause powder to flow into said die cavity, said suction beingapplied to said die cavity through said filter; c) isolating said filterfrom said powder in said die cavity; and d) compressing said powder insaid die cavity so as to form a compressed dosage form while said filteris isolated therefrom.

[0016] The invention also provides an apparatus for forming compresseddosage forms, comprising: a) a suction source; b) a die cavity having(i) a first port for placing said die cavity in flow communication withsaid suction source, whereby said suction source applies suction to saiddie cavity, and (ii) a second port for placing said die cavity in flowcommunication with a supply of powder, whereby said suction sourceassists said powder in flowing into said die cavity; (c) a filterdisposed between said suction source and said second port, wherebysuction is applied to said die cavity through said filter; and (d) apunch for compressing said powder in said die cavity so as to form saidcompressed dosage forms.

[0017] The invention also provides an apparatus for forming compresseddosage forms from a powder, comprising a) a die table having a pluralityof die cavities therein, said die cavities being arranged in multiple,concentric rows around the perimeter of said die table; b) punchesaligned with and insertable into said die cavities for compressing saidpowder into compressed dosage forms in each of said die cavities; and c)rollers aligned with each of said concentric rows of die cavities forpressing said punches into said die cavities, each roller being sizedsuch that the dwell time under compression of all of said punches isequal.

[0018] The invention also provides a rotary compression module forforming compressed dosage forms from a powder, comprising a) a singlefill zone; b) a single compression zone; c) a single ejection zone; d) acircular die table having a plurality of die cavities therein; and e)punches aligned with and insertable into said die cavities forcompressing said powder into compressed dosage forms in each of said diecavities; wherein the number of die cavities in said module is greaterthan the maximum number of die cavities that can be arranged in a singlecircle around the circumference of a similar die table having the samediameter as the circular die table, and wherein the dwell time undercompression of all of said punches is equal.

[0019] The invention further provides compressed dosage forms made froma powder having a minimum orifice diameter of flowablility greater thanabout 10 mm as measured by the Flowdex test, the relative standarddeviation in weight of said compressed dosage forms being less thanabout 2%, and made using a linear velocity at the die of at least about230 cm/sec.

[0020] The invention also provides compressed dosage forms made from apowder having a minimum orifice diameter of flowablility greater thanabout 15 mm as measured by the Flowdex test, the relative standarddeviation in weight of said compressed dosage forms being less thanabout 2%, and made using a linear velocity at the die of at least about230 cm/sec.

[0021] The invention also provides compressed dosage forms made from apowder having a minimum orifice diameter of flowablility greater thanabout 25 mm as measured by the Flowdex test, the relative standarddeviation in weight of said compressed dosage forms being less thanabout 2%, and made using a linear at the die velocity of at least about230 cm/sec.

[0022] The invention also provides compressed dosage forms made from apowder having a minimum orifice diameter of flowablility greater thanabout 10 mm as measured by the Flowdex test, the relative standarddeviation in weight of said compressed dosage forms being less thanabout 1%, and made using a linear velocity at the die of at least about230 cm/sec.

[0023] The invention also priovides compressed dosage forms made from apowder having a minimum orifice diameter of flowablility greater thanabout 10 mm as measured by the Flowdex test, the relative standarddeviation in weight of said compressed dosage forms being less thanabout 2%, and made using a linear velocity at the die of at least about115 cm/sec.

[0024] The invention also provides compressed dosage forms made from apowder having an average particle size of about 50 to about 150 micronsand containing at least about 85 percent by weight of a medicant, therelative standard deviation in weight of said compressed dosage formsbeing less than about 1%.

[0025] The invention also provides compressed dosage forms containing atleast about 85 percent by weight of a medicant and being substantiallyfree of water soluble polymeric binders, the relative standard deviationin weight of said compressed dosage forms being less than about 2%.

[0026] The invention also provides compressed dosage forms containing atleast about 85 percent by weight of a medicant and being substantiallyfree of water soluble polymeric binders, the relative standard deviationin weight of said compressed dosage forms being less than about 1%.

[0027] The invention also provides compressed dosage forms containing atleast about 85 percent by weight of a medicant selected from the groupconsisting of acetaminophen, ibuprofen, flurbiprofen, ketoprofen,naproxen, diclofenac, aspirin, pseudoephedrine, phenylpropanolamine,chlorpheniramine maleate, dextromethorphan, diphenhydramine, famotidine,loperamide, ranitidine, cimetidine, astemizole, terfenadine,fexofenadine, loratadine, cetirizine, antacids, mixtures thereof andpharmaceutically acceptable salts thereof, and being substantially freeof water soluble polymeric binders, the relative standard deviation inweight of said compressed dosage forms being less than about 2%.

[0028] The invention also provides compressed dosage forms containing atleast about 85 percent by weight of a medicant and being substantiallyfree of hydrated polymers, the relative standard deviation in weight ofsaid compressed dosage forms being less than about 2%.

[0029] The invention also provides compressed dosage forms containing atleast about 85 percent by weight of a medicant and being substantiallyfree of hydrated polymers, the relative standard deviation in weight ofsaid compressed dosage forms being less than about 1%.

[0030] The invention also provides compressed dosage forms containing atleast about 85 percent by weight of a medicant selected from the groupconsisting of acetaminophen, ibuprofen, flurbiprofen, ketoprofen,naproxen, diclofenac, aspirin, pseudoephedrine, phenylpropanolamine,chlorpheniramine maleate, dextromethorphan, diphenhydramine, famotidine,loperamide, ranitidine, cimetidine, astemizole, terfenadine,fexofenadine, loratadine, cetirizine, antacids, mixtures thereof andpharmaceutically acceptable salts thereof, and being substantially freeof hydrated polymers, the relative standard deviation in weight of saidcompressed dosage forms being less than about 2%.

[0031] The invention also provides a method of making a dosage formcontaining a first medicant, which comprises a) injecting through anozzle a flowable material containing said first medicant into a moldcavity; and b) hardening said flowable material into a molded dosageform having a shape substantially the same as the mold cavity.

[0032] The invention provides a method of making a molded dosage formwhich comprises a) heating a flowable material; b) injecting saidflowable material through an orifice into a mold cavity; and c)hardening said flowable material into a molded dosage form having ashape substantially the same as the mold cavity; wherein said hardeningstep (c) comprises cooling said flowable material and wherein said moldcavity is heated prior to said injecting step (b) and cooled during saidhardening step (c).

[0033] The invention also provides a method of coating a substrate,comprising the steps of: a) enclosing at least a portion of saidsubstrate in a mold cavity; b) injecting a flowable material into saidmold cavity so as to coat at least a portion of said substrate with saidflowable material; and c) hardening said flowable material to form acoating over at least a portion of said substrate.

[0034] The invention also provides a method of applying at least oneflowable material to a substrate having first and second portionscomprising: masking said first portion of said substrate; exposing saidsecond portion to a mold cavity; injecting said flowable material ontosaid second portion; and hardening said flowable material on said secondportion of said substrate.

[0035] The invention also provides a method of applying at least oneflowable material to a substrate having first and second portionscomprising: exposing said first portion to a first mold cavity;injecting said flowable material onto said first portion; hardening saidflowable material on said first portion of said substrate; retainingsaid first portion in said first mold cavity.

[0036] The invention provides a method of coating a substrate with firstand second flowable materials, comprising the steps of: a) enclosing afirst portion of said substrate in a first mold cavity; b) injecting afirst flowable material into said first mold cavity so as to coat saidfirst portion with said first flowable material; c) hardening said firstflowable material to form a coating over said first portion; d)enclosing a second portion of said substrate in a second mold cavity; e)injecting a second flowable material into said second mold cavity so asto coat said second portion with said second flowable material; and f)hardening said second flowable material to form a coating over saidsecond portion.

[0037] The invention provides an apparatus for molding substratescomprising a plurality of mold cavities, each mold cavity having aninternal surface and comprising an orifice for delivering flowablematerial to said mold cavity, said orifice being matable with a valvetip that in its closed position forms part of said internal surface.

[0038] The invention also provides an apparatus for molding substratescomprising a plurality of mold cavities, a heat source, a heat sink, anda temperature control system, said temperature control system comprisinga tubing system disposed proximal to said mold cavities and connected tosaid heat source and said heat sink for circulating heat transfer fluidthrough said heat source, through said heat sink, and proximal to saidmold cavities, such that said mold cavities may be heated and cooled bysaid heat transfer fluid.

[0039] The invention also provides a nozzle system for a moldingapparatus, comprising a nozzle and an ejector means, said nozzlesurrounding and being concentric with said ejector means.

[0040] The invention provides an apparatus for coating compressed dosageforms, comprising: a) a mold cavity for enclosing at least a firstportion of said compressed dosage form; b) means for injecting aflowable material into said mold cavity to coat at least said firstportion of said compressed dosage form with said flowable material; andc) means for hardening said flowable material so as to form a coatingover at least said first portion said compressed dosage form.

[0041] The invention also provides an apparatus for coating a compresseddosage form having a first portion and a second portion, comprising: a)a mold cavity for enclosing said first portion of said compressed dosageform; b) a nozzle for injecting a flowable material into said moldcavity to coat said first portion of said compressed dosage form withsaid flowable material; c) a temperature control system capable ofheating and cooling said mold cavity; and d) an elastomeric collet forsealing said second portion of said compressed dosage form while saidfirst portion of said compressed dosage form is being coated.

[0042] The invention also provides a molding module for molding coatingsonto compressed dosage forms, comprising a rotor capable of rotatingabout a central axis and a plurality of mold units mounted thereon, eachmold unit comprising: a) a mold cavity for enclosing at least a firstportion of said compressed dosage form; b) means for injecting aflowable material into said mold cavity to coat at least said firstportion of said compressed dosage form with said flowable material; andc) means for hardening said flowable material so as to form a coatingover at least said first portion said compressed dosage form.

[0043] The invention also provides a molding module for coating acompressed dosage form having a first portion and a second portion,comprising a rotor capable of rotating about a central axis and aplurality of mold units mounted thereon, each mold unit comprising: a) amold cavity for enclosing said first portion of said compressed dosageform; b) a nozzle for injecting a flowable material into said moldcavity to coat said first portion of said compressed dosage form withsaid flowable material; c) a temperature control system capable ofheating and cooling said mold cavity; and d) an elastomeric collet forsealing said second portion of said compressed dosage form while saidfirst portion of said compressed dosage form is being coated.

[0044] The invention also provides an apparatus for coating compresseddosage forms, comprising: a) a lower retainer comprising a plurality ofcollets mounted therein; b) a center mold assembly comprising first andsecond groups of insert assemblies mounted on opposing sides thereof,each of said insert assemblies of said first group aligned with andfacing one of said collets, said lower retainer and said center moldassembly mounted for relative movement so as to bring said first groupof insert assemblies into engagement with said collets; c) an upper moldassembly comprising upper insert assemblies mounted therein, each ofsaid upper insert assemblies aligned with and facing one of said insertassemblies of said second group, said upper mold assembly and saidcenter mold assembly mounted for relative movement so as to bring saidupper insert assemblies into engagement with said second group of insertassemblies; d) a supply of flowable material; and e) a first passageplacing said supply of flowable material in flow communication with saidfirst and second group of insert assemblies, and a valve actuatorassembly for controlling the flow of said flowable material to saidfirst and second groups of insert assemblies.

[0045] The invention also provides a dosage form comprising a substratehaving an injection molded coating surrounding at least a portion of thesubstrate.

[0046] The invention also provides a dosage form comprising a substratehaving a thermal cycle molded material disposed on at least a portion ofthe substrate.

[0047] The invention also provides a dosage form comprising a substratehaving a coating thereon, said coating having a thickness of about 100to about 400 microns; the relative standard deviation in thickness ofsaid coating being less than 30%; wherein said coating is substantiallyfree of humectants.

[0048] The invention also provides a dosage form comprising a tablethaving a coating thereon, said coating having a thickness of about 100to about 400 microns, wherein the relative standard deviation inthickness of said dosage form is not more than about 0.35%; and whereinsaid coating is substantially free of humectants.

[0049] The invention also provides an apparatus for transferringsubstrates from a first location to a second location, comprising: a) aflexible conveying means; b) a plurality of transfer units mounted tosaid conveying means, said transfer units being capable of holding saidsubstrates; c) a cam track defining a path between said first and secondlocations; and d) means for driving said conveying means along said camtrack.

[0050] The invention also provides an apparatus for transferringsubstrates from a first operating module comprising a first rotoradapted to carry said substrates around a first circular path to asecond operating module comprising a second rotor adapted to carry saidsubstrates around a second circular path, said apparatus comprising aflexible conveying means traversing a third path, a first portion ofsaid third path being coincident with a portion of said first circularpath and a second portion of said third path being coincident with aportion of said second circular path.

[0051] The invention also provides a method for making an insert,comprising the steps of: a) injecting a starting material in flowableform comprising a medicant and a thermal setting material into a moldingchamber having a shape; b) solidifying said starting material so as toform a solid insert having the shape of said molding chamber; and c)ejecting said solid insert from said molding chamber, wherein said stepsoccur during rotation of said molding chambers about a central axis.

[0052] The invention provides an apparatus for molding substrates from astarting material in flowable form, comprising a plurality of moldingchambers and a plurality of nozzles aligned with said molding chambers,said molding chambers and said nozzles mounted on a rotor capable ofrotation about a central axis, said nozzles being displaceable in adirection parallel to said central axis, such that as said rotorrotates, said nozzles engage and disengage said molding chambers.

[0053] The invention also provides a dosage form comprising a medicant,said dosage form prepared by molding a flowable material, said dosageform having no more than one axis symmetry and being substantially freevisible defects.

BRIEF DESCRIPTION OF THE DRAWINGS

[0054]FIGS. 1A and 1B are examples of dosage forms made according to theinvention.

[0055]FIG. 2 is a flow chart an embodiment of the method of theinvention.

[0056]FIG. 3 is a plan view, partially schematic, of a system formanufacturing dosage forms according to the invention.

[0057]FIG. 4 is an elevational view of the system shown in FIG. 3.

[0058]FIG. 5 is a three dimensional view of a compression module andtransfer device according to the invention.

[0059]FIG. 6 is top view of a portion of the compression module shown inFIG. 5.

[0060]FIG. 7 depicts the path of one row of punches of a compressionmodule during a revolution of the compression module.

[0061]FIG. 8 depicts the path of another row of punches of thecompression module during a revolution of the compression module.

[0062]FIG. 9 is a partial cross-section of a compression module duringcompression.

[0063]FIG. 10 is a cross-section take through line 10-10 of FIG. 9.

[0064]FIG. 11 is a cross-section taken through line 11-11 of FIG. 10.

[0065]FIG. 12 is an enlarged view of the die cavity area circled in FIG.11.

[0066]FIG. 12A shows another embodiment of a die cavity of thecompression module.

[0067]FIG. 13 is a top view of the fill zone of the compression module.

[0068]FIG. 14 is a cross-sectional view of a portion of the fill zone ofthe compression module.

[0069]FIG. 15 is a cross section taken through line 15-15 of FIG. 6.

[0070]FIG. 16 is a view taken along an are of the compression moduleduring compression.

[0071] FIGS. 17A-C illustrate one embodiment of a “C” frame for thecompression rollers.

[0072] FIGS. 18A-C illustrate another embodiment of a “C” frame for thecompression rollers.

[0073] FIGS. 19A-C illustrate a preferred embodiment of a “C” frame forthe compression rollers.

[0074]FIG. 20 is a top view of the purge zone and the fill zone of thecompression module.

[0075]FIG. 21 is a cross-section taken through line 21-21 of FIG. 20.

[0076]FIG. 22 is a cross-section taken through line 22-22 of FIG. 20.

[0077]FIG. 23 illustrates an embodiment of a powder recovery system forthe compression module.

[0078]FIG. 24 is a cross-section taken along line 24-24 of FIG. 23.

[0079]FIG. 25 shows an alternative embodiment of a powder recoverysystem for the compression module.

[0080] FIGS. 26A-C illustrate one embodiment of a thermal cycle moldingmodule according to the invention in which dosage forms per se are made.

[0081] FIGS. 27A-C illustrate another embodiment of a thermal cyclemolding module in which a coating is applied to a substrate.

[0082] FIGS. 28A-C illustrate a preferred embodiment of a thermal cyclemolding module in which a coating is applied to a substrate.

[0083]FIG. 29 is a three dimensional view of a thermal cycle moldingmodule according to the invention.

[0084]FIG. 30 depicts a series of center mold assemblies in a thermalcycle molding module.

[0085]FIG. 31 is a cross-section taken along line 31-31 of FIG. 30.

[0086] FIGS. 32-35 depict the opening, rotation and closing of thecenter mold assembly with the lower retainer and upper mold assembly.

[0087]FIGS. 36 and 37 are cross-sectional views of a lower retainer of athermal cycle molding module.

[0088]FIGS. 38 and 39 are top views of an elastomeric collet of a lowerretainer.

[0089]FIG. 40 shows a preferred cam system for the center mold assemblyof the thermal molding module.

[0090]FIG. 41 is a cross-section of the center mold assembly showing oneembodiment of a valve actuator assembly therefor.

[0091]FIG. 42 is a cross-section of the center mold assembly showing oneembodiment of an air actuator assembly therefor.

[0092]FIGS. 43 and 46 are cross-sectional views of a portion of thecenter mold assembly showing first and second manifold plates.

[0093]FIG. 44 is a cross-section taken along line 44-44 of FIG. 43.

[0094]FIG. 45 is a cross-section taken along line 45-45 of FIG. 43.

[0095]FIG. 47 is a cross-section taken along line 47-47 of FIG. 46.

[0096] FIGS. 48-50 are cross-sectional views of a preferred nozzlesystem of a center mold assembly.

[0097]FIG. 51 is a cross-sectional view of an upper mold assembly of thethermal cycle molding module showing a cam system thereof.

[0098] FIGS. 52-54 are cross-sectional view of the upper mold assemblyand the center mold assembly of the thermal cycle molding module.

[0099]FIGS. 55 and 56 illustrate one embodiment of a temperature controlsystem for the thermal cycle molding module.

[0100] FIGS. 57-59 depict another embodiment of a temperature controlsystem for the thermal cycle molding module.

[0101] FIGS. 60-62 show a preferred embodiment of the temperaturecontrol system for the thermal cycle molding module.

[0102] FIGS. 63-65 illustrate a rotary pinch valve system suitable foruse in the temperature control system of the thermal cycle moldingmodule.

[0103]FIG. 68 is a top view of a transfer device according to theinvention.

[0104]FIG. 69 is a cross-section taken along line 69-69 of FIG. 68.

[0105] FIGS. 70-74 illustrate a preferred embodiment of a transfer unitof a transfer device according to the invention.

[0106]FIG. 75 is a cross-section taken along line 75-75 of FIG. 68.

[0107]FIG. 76 shows a transfer device according to the inventiontransferring an insert from a thermal setting molding module to acompression module.

[0108]FIG. 77 is a top view of a rotational transfer device according tothe invention.

[0109]FIG. 78 is cross-sectional view of a rotational transfer deviceaccording to the invention.

[0110]FIG. 79 depicts transfer of compressed dosage forms from acompression module to a thermal cycle molding module via a rotationaltransfer device according to the invention.

[0111]FIG. 80 is a further cross-sectional view of a rotational transferdevice according to the invention.

[0112] FIGS. 81A-G illustrate operation of a rotational transfer deviceaccording to the invention, FIGS. 81E, 81F, and 81G being rear views ofFIGS. 81B, 81C, and 81D, respectively.

[0113]FIG. 82 is a side view of a thermal setting molding moduleaccording to the invention.

[0114]FIG. 82A is a cross-section taken along line A-A of FIG. 82.

[0115]FIG. 83 is a front view of a thermal setting molding moduleaccording to the invention.

[0116]FIG. 84 is another front view of a thermal setting molding moduleaccording to the invention.

[0117] FIGS. 85A-D illustrate operation of the thermal setting moldingmodule.

[0118]FIG. 86 is a cross-sectional view of a preferred thermal settingmolding module according to the invention.

[0119]FIGS. 87 and 88 illustrate ejection of an insert from a thermalsetting molding module.

DESCRIPTION OF PREFERRED EMBODIMENTS Overview

[0120] The methods, systems, and apparatuses of this invention can beused to manufacture conventional dosage forms, having a variety ofshapes and sizes, as well as novel dosage forms that could not have beenmanufactured heretofore using conventional systems and methods. In itsmost general sense, the invention provides: 1) a compression module formaking compressed dosage forms from compressible powders, 2) a thermalcycle molding module for making molded dosage forms, or for applying acoating to a substrate, 3) a thermal setting molding module for makingmolded dosage forms, which may take the form of inserts for dosageforms, 4) a transfer device for transferring dosage forms from onemodule to another, and 5) a process for making dosage forms comprisingat least two of the above modules linked together, preferably via thetransfer device. Such process may be run on a continuous or indexingbasis.

[0121]FIG. 2 is a flow chart illustrating a preferred method forproducing certain dosage forms according to the invention, which employsall of the operating modules linked into a continuous process. Inparticular, the method reflected in FIG. 2 produces a dosage form 10comprising a molded coating 18 on the outside surface of a compresseddosage form 12 also containing an insert 14 as shown in FIG. 1A. FIGS. 3and 4 depict a preferred system for practicing the method illustrated inFIG. 2. FIG. 1B illustrates an alternative dosage form 10′ that may bemade according to the invention comprising a molded coating 18′ over acompressed dosage form 12′. It may be appreciated from FIG. 1B that thecoating and the compressed dosage form need not have the same shape.

[0122] By way of overview, this preferred system 20 comprises acompression module 100, a thermal cycle molding module 200 and atransfer device 300 for transferring a compressed dosage form made inthe compression module 100 to the thermal cycle molding module 200 asshown in FIGS. 3 and 4. Linkage of the compression module, transferdevice, and the thermal cycle molding module in this manner results in acontinuous, multi-station system. Compression is accomplished in thefirst module, molding of a coating around the resulting compresseddosage form is performed in the second module, and transfer of thedosage form from one module to the other is accomplished by the transferdevice.

[0123] In other preferred embodiments, the system 20 also includes athermal setting molding module 400 for forming a molded dosage form,which may comprise the final dosage form or be an insert forincorporation into another dosage form. In a preferred embodiment, theinsert comprises a high potency additive. The invention is not limitedto the type or nature of insert. Rather, the term insert is used simplyto denote a pellet-type component embedded in another dosage form. Suchan insert may itself contain a medicant, and retains its shape whilebeing placed within the powder.

[0124] When used in the preferred, linked system comprising acompression module, the insert is formed in Step B of FIG. 2. Followingthis, the insert is inserted into uncompressed powder within compressionmodule 100. After insertion the powder and insert are compressed (Step Cof FIG. 2). The thermal setting molding module 400 can be separate fromor part of the compression module 100. If the thermal setting moldingmodule is separate from the compression module 100, a transfer device700 can be used to transfer the insert from the thermal setting moldingmodule 400 to the compression module 100.

[0125] The linked system for creating dosage forms, as well as eachindividual operating module, provide many processing advantages. Theoperating modules may be used separately or together, in differentsequences, depending on the nature of the dosage form desired. Two ormore of the same operating modules may be used in a single process. Andalthough the apparatuses, methods and systems of this invention aredescribed with respect to making dosage forms, it will be appreciatedthat they can be used to produce non-medicinal products as well. Forexample, they may be used to make confections or placebos. The moldingmodule can be used with numerous natural and synthetic materials with orwithout the presence of a medicant. Similarly, the compression modulecan be used with various powders with or without drug. These examplesare provided by way of illustration and not by limitation, and it willbe appreciated that the inventions described herein have numerous otherapplications.

[0126] When linked in a continuous process, the operating modules caneach be powered individually or jointly. In the preferred embodimentshown in FIGS. 3 and 4, a single motor 50 powers the compression module100, the thermal cycle molding module 200, and the transfer device 300.The motor 50 can be coupled to the compression module 100, the thermalcycle molding module 200 and the transfer device 300 by any conventionaldrive train, such as one comprising gears, gear boxes, line shafts,pulleys, and/or belts. Of course, such a motor or motors can be used topower other equipment in the process, such as the dryer 500 and thelike.

Compression Module

[0127] FIGS. 5-25 generally depict the compression module 100. FIG. 5depicts a three dimensional view of the compression module 100 and thetransfer device 300. The compression module 100 is a rotary device thatperforms the following functions: feeding powder to a cavity, compactingthe powder into a compressed dosage form and then ejecting thecompressed dosage form. When the compression module is used inconjunction with the thermal cycle molding module 200, upon ejectionfrom the compression module the compressed dosage form may betransferred to the molding module either directly or through the use ofa transfer device, such as transfer device 300 described below.Optionally, an insert formed by another apparatus, such as the thermalsetting molding module 400 described below, can be inserted into thepowder in the compression module before the powder is compressed intothe compressed dosage form.

[0128] In order to accomplish these functions the compression module 100preferably has a plurality of zones or stations, as shown schematicallyin FIG. 6, including a fill zone 102, an insertion zone 104, acompression zone 106, an ejection zone 108 and a purge zone 110. Thus,within a single rotation of the compression module 100 each of thesefunctions are accomplished and further rotation of the compressionmodule 100 repeats the cycle.

[0129] As shown generally in FIGS. 4, 5, 9 and 14, the rotary portion ofthe compression module generally includes an upper rotor 112, a circulardie table 114, a lower rotor 116, a plurality of upper 118 and lower 120punches, an upper cam 122, a lower cam 123 and a plurality of dies 124.FIG. 9 depicts a portion of the rotors 112, 116, and die table 114 froma side view, while FIG. 14 depicts a vertical cross-section through therotors 112, 116 and die table 114. FIG. 16 depicts an annularcross-section through rotors 112, 116 and die table 114. FIGS. 7 and 8are two dimensional representations of the circular path the punches118, 120 follow as they rotate with respect to the cams 122, 123 withthe rotors removed from the drawing for purposes of illustration. Theupper rotor 112, die table 114 and lower rotor 116 are rotatably mountedabout a common shaft 101 shown in FIG. 3.

[0130] Each of the rotors 112, 116 and the die table 114 include aplurality of cavities 126 which are disposed along the circumferences ofthe rotors and die table. Preferably, there are two circular rows ofcavities 126 on each rotor, as shown in FIG. 6. Although FIG. 6 onlyshows the die table 114, it will be appreciated that the upper 112 andlower rotors 116 each have the same number of cavities 126. The cavities126 of each rotor are aligned with a cavity 126 in each of the otherrotors and the die table. There are likewise preferably two circularrows of upper punches 118 and two circular rows of lower punches 120, asbest understood with reference to FIGS. 4, 5, 9 and 14. FIG. 7 depictsthe outer row of punches, and FIG. 8 illustrates the inner row ofpunches.

[0131] Conventional rotary tablet presses are of a single row design andcontain one powder feed zone, one compression zone and one ejectionzone. This is generally referred to as a single sided press sincetablets are ejected from one side thereof. Presses offering a higheroutput version of the single row tablet press employing two powder feedzones, two tablet compression zones and two tablet ejection zones arecommercially available. These presses are typically twice the diameterof the single sided version, have more punches and dies, and ejecttablets from two sides thereof. They are referred to as double sidedpresses.

[0132] In a preferred embodiment of the invention the compression moduledescribed herein is constructed with two concentric rows of punches anddies. This double row construction provides for an output equivalent totwo single side presses, yet fits into a small, compact space roughlyequal to the space occupied by one conventional single sided press. Thisalso provides a simplified construction by using a single fill zone 102,a single compression zone 106, and a single ejection zone 108. A singleejection zone 108 is particularly advantageous in the linked process ofthe invention, because the complexity of multiple transfer devices 300,700 having double sided construction is avoided. Of course, acompression module with one row or more than two rows can also beconstructed.

[0133] The upper punches 118 illustrated in FIGS. 7-9 extend from abovethe cavities 126 in the upper rotor 112 through the cavities 126 in theupper rotor and, depending on their position, either proximal to orwithin the cavities 126 of the die table 114. Similarly, the lowerpunches extend from beneath the cavities 126 in the lower rotor 116 andinto the cavities 126 in the die table 114, as is also best understoodwith reference to FIGS. 7-9. The cavities 148 in the upper and lowerrotors serve as guides for the upper 118 and lower 120 punchesrespectively.

[0134] Disposed within each of the cavities 126 of the die table is adie 124. FIGS. 9-14 depict the dies 124 and cross sections through thedie table 114. FIG. 9 is a partial cross section of the die table 114taken along an arc through a portion of the die table 114. FIG. 14 is across section taken vertically along a radius though the die table 114.Because there are preferably two circular rows of dies, the two rows ofdies lie along two concentric radii, as best understood with referenceto FIGS. 6 and 14.

[0135] Preferably, the dies 124 are metallic, but any suitable materialwill suffice. Each die 124 may be retained by any of a variety offastening techniques within the respective cavity 126 of the die table114. For example, the dies 124 may be shaped so as to have a flange 128that rests on a seating surface 130 formed in the die table 114 and apair of o-rings 144 and grooves 146, as best understood with referenceto FIG. 10. FIG. 10 is an enlarged view of the dies shown in FIG. 9without the upper punches inserted into the dies. It will be appreciatedthat all the dies 124 are similar in construction.

[0136] Each die 124 comprises a die cavity 132 for receiving the upperand lower punches 118, 120. The die cavities 132 and the lower punches118 that extend a distance into the die cavities 132 define the volumeof powder to be formed into the compressed dosage form and hence thedosage amount. Thus, the size of die cavity 132 and the degree ofinsertion of the punches into the die cavities 132 can be appropriatelyselected or adjusted to obtain the proper dosage.

[0137] In a preferred embodiment, the die cavities are filled using theassistance of a vacuum. Specifically, each die 124 has at least one port134 disposed within it, as shown in FIGS. 10, 11, and 12. Disposedwithin or proximal to each port 134 is a filter 136. The filters 136 aregenerally a metallic mesh or screen appropriately sized for theparticles that will be flowing through the die cavities 134. Onesurprising feature of the present compression module is that the filtersmay comprise screens having a mesh size larger than the average particlesize of the powder, which is typically about 50 to about 300 microns.While the filters 136 are preferably metallic, other suitable materialsmay be employed, such as fabrics, porous metals or porous polymerconstructions. The filter 136 may be a single stage or multi-stagefilter, but in the preferred embodiment the filter 136 is a single stagefilter. The filter may also be located anywhere in the vacuum passages.Alternatively, it can be located externally to the die table as shown inFIG. 12A. In a preferred embodiment the filters are located in the diewall ports 134 as close as possible to the punches. See FIG. 12. Thiscreates the least amount of residue requiring purging and subsequentrecycling in the purge zone 110 and powder recovery system. The top ofthe die cavity 132 is preferably open and defines a second port.

[0138] The die table 114 preferably comprises channels 138 within itthat circle each pair of dies 124 and extend to the ports 134, as bestshown in FIG. 11. In addition the die table 114 preferably has aplurality of relatively small openings 140 on its outer periphery thatconnect each of the respective channels 138, so that the die cavitiescan be connected to a vacuum source (or suction source). Disposed alonga portion of the periphery of the die table 114 are a stationary vacuumpump 158 and a vacuum manifold 160, which make up a portion of the fillzone 102, as shown in FIG. 14. The vacuum pump 158 provides a source ofvacuum for pulling powder into the die cavities 132. The vacuum pump 158is connected to the vacuum manifold 160 with suitable tubing 162. Thevacuum manifold 160 is aligned with the openings 140. As the die table114 rotates during operation of the vacuum pump 158, the openings 140 inthe die table 114 become aligned with the vacuum manifold 160 and avacuum is formed through the respective channel 138 and die cavity 132.

[0139] Vacuum is accordingly applied through the respective ports 134and channels 138 to pull powder into the die cavity 132. See FIGS. 20and 21. A seal can be created around the ports 134 and the channel 138proximal to the port 134 with any of a variety of techniques. In thepreferred embodiment shown a seal is created using o-rings 144 andgrooves 146.

[0140] Conventional tablet presses rely on highly flowable powders andthe effects of gravity to fill the die cavity. The performance of thesemachines in terms of fill accuracy and press speed are thereforeentirely dependent on the quality and flowabilty of the powder. Sincenon-flowing and poorly flowing powders cannot be effectively run onthese machines these materials must be wet granulated in a separatebatch process which is costly, time consuming, and energy inefficient.

[0141] The preferred vacuum fill system described is advantageous overconventional systems in that poorly flowing and non-flowing powders canbe run at high speed and high accuracy without the need for wetgranulation. In particular, powders having a minimum orifice diameter offlowability greater than about 10, preferably 15, more preferably 25 mm,as measured by the Flowdex test, may be successfully compressed intodosage forms in the present compression module. The Flowdex test isperformed as follows. The minimum orifice diameter is determined using aFlodex Apparatus Model 21-101-050 (Hanson Research Corp., Chatsworth,Calif.), which consists of a cylindrical cup for holding the powdersample (diameter 5.7 cm, height 7.2 cm), and a set of interchangeabledisks, each with a different diameter round opening at the center. Thedisks are attached to the cylindrical cup to form the bottom of the“cup.” For filling, the orifice is covered with a clamp. Minimum orificediameter measurements are performed using 100 g samples of powder. A 100g sample is placed into the cup. After 30 seconds the clamp is removed,and the powder allowed to flow out of the cup through the orifice. Thisprocedure is repeated with increasingly smaller orifice diameters untilthe powder no longer flows freely through the orifice. The minimumorifice diameter is defined as the smallest opening through which thepowder flows freely.

[0142] Moreover, compression of such relatively poorly flowing powdersmay be done while operating the compression module at high speeds, i.e.,the linear velocity of the dies is typically at least about 115 cm/sec,preferably at least about 230 cm/sec. In addition, weight variations inthe final compressed dosage forms are significantly less, since vacuumfilling of the die cavity causes a densifying effect on the powder inthe die cavity. This minimizes the density variations powders typicallyexhibit due to compaction, static head pressure variation, or lack ofblend homogeneity. The relative standard deviation in weight ofcompressed dosage forms made according to the invention is typicallyless than about 2%, preferably less than about 1%.

[0143] In addition, better content uniformity can also be achieved withthe present vacuum fill system, since little mechanical agitation isrequired to cause the powder to flow into the die cavity. Inconventional tablet presses, the mechanical agitation required to assuredie filling has the adverse effect of segregating small from largeparticles.

[0144] Known powder filling equipment employ vacuum to fill uncompressedpowders into capsules or other containers. See. For example, Aronson,U.S. Pat. No. 3,656,518 assigned to Perry Industries, Inc. However,these systems have filters that are always in contact with the powderand therefore unsuitable for adaptation to compression machines. Forceson the order of 100 kN can be experienced during compression of powdersinto dosage forms. Such high forces would damage the filters. U.S. Pat.No. 4,292,017 and U.S. Pat. No. 4,392,493 to Doepel describe a highspeed rotary tablet compression machine which uses vacuum die filling.However separate turntables are used for filling and compression. Diesare filled on the first turntable and thereafter transferred to aseparate turntable for compression. Advantageously, according to theinvention, the filters are protected during compression, since the lowerpunches move above the filter port prior to the die cavities enteringthe compression zone.

[0145] Powder is fed into the die cavities 132 in the fill zone 102. Thepowder may preferably consist of a medicant optionally containingvarious excipients, such as binders, disintegrants, lubricants, fillersand the like, as is conventional, or other particulate material of amedicinal or non-medicinal nature, such as inactive placebo blends fortableting, confectionery blends, and the like. One particularlypreferred formulation comprises medicant, powdered wax (such as shellacwax, microcrystalline wax, polyethylene glycol, and the like), andoptionally disintegrants and lubricants and is described in more detailin commonly assigned co-pending U.S. patent application Ser. No. ______,entitled “Immediate Release Tablet” (attorney docket number MCP 274)which is hereby incorporated by reference.

[0146] Suitable medicants include for example pharmaceuticals, minerals,vitamins and other nutraceuticals. Suitable pharmaceuticals includeanalgesics, decongestants, expectorants, antitussives, antihistamines,gastrointestinal agents, diuretics, bronchodilators, sleep-inducingagents and mixtures thereof. Preferred pharmaceuticals includeacetaminophen, ibuprofen, flurbiprofen, ketoprofen, naproxen,diclofenac, aspirin, pseudoephedrine, phenylpropanolamine,chlorpheniramine maleate, dextromethorphan, diphenhydramine, famotidine,loperamide, ranitidine, cimetidine, astemizole, terfenadine,fexofenadine, loratadine, cetirizine, antacids, mixtures thereof andpharmaceutically acceptable salts thereof. More preferably, the medicantis selected from the group consisting of acetaminophen, ibuprofen,pseudoephedrine, dextromethorphan, diphenhydramine, chlorpheniramine,calcium carbonate, magnesium hydroxide, magnesium carbonate, magnesiumoxide, aluminum hydroxide, mixtures thereof, and pharmaceuticallyacceptable salts thereof.

[0147] The medicant(s) is present in the dosage form in atherapeutically effective amount, which is an amount that produces thedesired therapeutic response upon oral administration and can be readilydetermined by one skilled in the art. In determining such amounts, theparticular medicant being administered, the bioavailabilitycharacteristics of the medicant, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.Preferably, the compressed dosage form comprises at least about 85weight percent of medicant.

[0148] If the medicant has an objectionable taste, and the dosage formis intended to be chewed or disintegrated in the mouth prior toswallowing, the medicant may be coated with a taste masking coating, asknown in the art. Examples of suitable taste masking coatings aredescribed in U.S. Pat. No. 4,851,226, U.S. Pat. No. 5,075,114, and U.S.Pat. No. 5,489,436. Commercially available taste masked medicants mayalso be employed. For example, acetaminophen particles which areencapsulated with ethylcellulose or other polymers by a coaccervationprocess may be used in the present invention. Coaccervation-encapsulatedacetaminophen may be purchased commercially from Eurand America, Inc.Vandalia, Ohio, or from Circa Inc., Dayton, Ohio.

[0149] Suitable excipients include fillers, which include water-solublecompressible carbohydrates such as dextrose, sucrose, mannitol,sorbitol, maltitol, xylitol, lactose, and mixtures thereof, waterinsoluble plasticly deforming materials such as microcrystallinecellulose or other cellulosic derivatives, water-insoluble brittlefracture materials such as dicalcium phosphate, tricalcium phosphate,and the like; other conventional dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like; sweeteners suchas aspartame, acesulfame potassium, sucralose, and saccharin;lubricants, such as magnesium stearate, stearic acid, talc, and waxes;and glidants, such as colloidal silicon dioxide. The mixture may alsoincorporate pharmaceutically acceptable adjuvants, including, forexample, preservatives, flavors, antioxidants, surfactants, and coloringagents. Preferably however, the powder is substantially free of watersoluble polymeric binders and hydrated polymers.

[0150] Included within the fill zone 102 may be a doctor blade 131 asshown in FIG. 9 that “doctors” or levels the powder along the die table114 as the die table 114 rotates through the fill zone 102. Inparticular, as a filled die cavity 132 rotates past the powder bed, thedie table 114 passes against the doctor blade 131 (as shown in FIG. 9)which scrapes the surface of the die table 114 to assure the preciseleveling and measurement of powder filling the die cavity 132.

[0151] After the punches leave the fill zone 102 they enter theinsertion zone 104. In this zone the lower punches 120 may retractslightly to allow for an optional insert to be embedded into the softuncompressed powder in the die cavity 132 via a transfer device 700.This mechanism is described in greater detail below.

[0152] After continued rotation and before entering the compression zone106, the upper punch 118 is pushed into the die cavity 132 by the camtrack 122 as shown in FIGS. 7, 8 and 16. Following this, the upper andlower punches 118, 120 engage the first stage rollers 180 as shown inFIG. 16 where force is applied to the powder via the first stagerollers. After this initial compression event, the punches enter thesecond stage rollers 182 as shown in FIG. 16. The second stage rollers182 drive the punches 118, 120 into the die cavity 132 to furthercompress the powder into the desired compressed dosage form. Once pastthe compression zone the upper punches retract from the die cavity 132and the lower punches begin to move upward prior to entering theejection zone 108.

[0153] Because the distances traveled by the outer and inner rows ofpunches along their respective circular paths differ, the sizes of therollers 180 and 182 that activate each row differ. This enablescompression of the inner and outer rows to be simultaneous. Inparticular, the rollers that activate the inner row are smaller indiameter than the rollers that activate the outer row (as shown in FIG.15), but the inner and outer rollers have their greatest diameter alongthe same radial line. Thus, the outer row punches and inner row puncheswill each begin to be compressed at the same time, thus entering the diecavities simultaneously. By assuring the same dwell time undercompression, consistency of compressed dosage form thickness betweeninner and outer rows is assured. This thickness control is particularlyimportant should the compressed dosage forms be subjected to subsequentoperations, such as the application of coatings and the like.

[0154]FIGS. 17, 18, and 19 are three possible geometries for thecompression frame on which the compression rollers are mounted. FIG. 17illustrates one possible “C” geometry for the compression frame. Asshown in FIGS. 17B and 17C deflection of the compression frame displacesthe rollers by the amount “Δ” under the significant forces ofcompression (The double row compression module illustrated herepreferably has twice this rating or 200 kN.) An advantage of the framegeometry depicted in FIGS. 17A through 17C is that the displacement A isparallel to the radial axis of the compression rollers 182. This slightdeflection can easily be compensated for by thickness controls on themachine. However, as shown in FIG. 17A, the frame occupies a significantamount of space. Accordingly there is less room for other equipment tobe mounted on or near the compression module (this is represented byangle φ).

[0155]FIGS. 18A through 18C illustrate an alternate “C” frame geometry.This arrangement has the advantage of occupying significantly less spacethan the arrangement outlined in FIGS. 17A through 17C. However in thisembodiment, deflection of the compression frame displaces the rollersout of the horizontal plane. This is represented by angle θ in FIG. 18C,θ increases as the load increases. The net effect is an inconsistencybetween inner and outer row compressed dosage form thickness that alsovaries with compression force.

[0156]FIGS. 19A through 19D illustrate a preferred embodiment of thecompression frame. As shown in FIG. 19D, the frame comprises a throat179 and two arms 178. The arms 178 forms an oblique angle Ω with respectto the axial axis of the rollers A-A. As shown in FIGS. 19B and 19Ddespite deflection of the frame anhd displacement A of the rollers, therollers remain horizontal. An additional advantage of this constructionis a significantly greater free space angle φ, as shown in FIG. 19A.This compression frame configuration can also advantageously pivot aboutan axis away from the compression module to allow for access or removalof the die table.

[0157] Following the formation of the compressed dosage form in thecompression zone 106, the respective die cavity 132 rotates to ejectionzone 108 as shown in FIG. 6. The upper punches 118 move upward due tothe slope of the cam tracks 122 as shown in FIGS. 7, 8, and 16 and outof the die cavities. The lower punches 120 move upward and into the diecavities 132 until eventually the lower punches 120 eject the compresseddosage form out of the die cavity 132, and optionally into a transferdevice 300 as shown in FIG. 6.

[0158] In the purge zone 110, excess powder is removed from the filters136 after the compressed dosage form has been ejected from the diecavities 132. This cleans the filters before the next filling operation.The purge zone 110 accomplishes this by blowing air through or placingsuction pressure on the filters 136 and channels 138.

[0159] In a preferred embodiment the purge zone 110 includes astationary positive pressure source 190, such as an air pump orpressurized air bank, and a pressure manifold 192, as shownschematically in FIG. 12. The pressure manifold 192 may be disposedproximal to the periphery of the die table 114 and between thecompression zone 106 and the fill zone 102, as best understood withreference to FIGS. 20 and 22. The pressure 10 manifold 192 preferablyhas at least one port 194 (although any number of ports can be used)that can be placed in fluid communication with the filters as the dietable 114 rotates. Pressure source 190 applies pressure through tubing196 and the pressure manifold 192 to each respective channel 138 and diecavity 132 as the die table 114 rotates and the openings 140 becomealigned with the pressure manifold ports 194, as shown in FIGS. 20 and22. It will be appreciated from FIGS. 7 and 8 that in the purge zone 110the upper punches 118 are removed from the die cavities 132 and thelower punches 120 are disposed beneath the filters 136, so that pressurecan be applied through the openings 140 as shown in FIG. 22. When thelower punch 120 is inserted into the die cavity 132 above the filters136 and die ports 134, die cavity 132 is disconnected from the vacuumsource 142, and vacuum is no longer exerted on the powder.

[0160] The positive pressure cleans out the filters to remove anybuildup of powder by transmitting pressurized air from the pressuremanifold through the channels and through the die cavities. Thepressurized air blows the powder up through the top of the die cavitiesto a collection manifold 193, shown in FIGS. 22, 24 and 25. From thecollection manifold, the powder can be sent to a collection chamber orthe like and if desired reused.

[0161] In order to increase the efficiency of the purge zone 110, thepurge zone 110 may further include a suction source 197 that appliessuction to the collection manifold 193 as shown in FIG. 22 and acollection chamber 193 that receives the powder from the suction source197.

[0162] If desired the purge zone 110 can include a recovery system torecover the removed powder and send it back to hopper 169 or the powderbed 171. This is advantageous because it minimizes waste. One embodimentof the recovery system is depicted in FIGS. 23 and 24. The recoverysystem feeds the purged powder into the die cavities 132 prior to theirarrival at the fill zone 102. In this embodiment, the recovery systemincludes shoe block 195, a blower 197, a cyclone receiver 199, adelivery manifold 198, and an agitator 191. The shoe block 195 isdisposed about and contacts a portion of the periphery of the die table114 between the pressure manifold 192 and the fill zone 102 as shown inFIG. 23. The shoe block 195 may be spring loaded by springs 189 so thatit fits tightly against the die table 114 as the die table 114 rotatespast it. The shoe block 195 is aligned with the openings 140 in the dietable 114 to create a pressure seal between the openings 140 and theshoe block 189. This pressure seal prevents purged powder in the diecavities 132 from being blown back out of the die cavities. Alternately,shoe block 195 can be dispensed with if the lower punches 120 are movedupward to cover the die ports 134 and then moved down again prior toentering the fill zone 102.

[0163] The blower 197 shown in FIG. 24 is coupled to the collectionmanifold 193 to pull powder from the die cavities 132. The blower 197sends purged powder from the collection manifold 193 to the cyclone dustseparator 199, which operates at a partial vacuum. The cyclone dustseparator 199 collects the purged powder and sends it to the deliverymanifold 198 as shown in FIG. 24. A filter bag dust separator can besubstituted for the cyclone dust separator. Once the dust is separatedfrom the air stream 199 it falls into the delivery manifold 198, asshown in FIG. 24

[0164] The delivery manifold 198 is disposed just above the die table114 so that as the die table 114 rotates, the top of the die table 114comes into contact with the delivery manifold 198, creating a pressureseal between the delivery manifold 198 and the die table 114. The diecavities are open to the delivery manifold 198 as shown in FIG. 24 sothat purged powder can flow into the die cavities by gravity or othermeans such as an optional vacuum source (not shown). The agitator 191rotates within the delivery manifold 198 to direct the purged powder tothe die cavities 132.

[0165] In operation, the die table 114 rotates proximal to the pressuremanifold 192 and beneath the collection manifold 193. As describedabove, pressurized air is sent through the openings 140 in the peripheryof the die table and vacuum is applied to the collection manifold 193and the two together cause powder to flow from the channels 138 and thedie cavities 132 as shown in FIG. 24 to the collection manifold 193.

[0166] From the collection manifold 193, the purged powder flows to thecyclone dust separator 199 where the purged powder is directed to theagitator 191 and the delivery manifold 198. The die table 114 continuesto rotate so that the purged die cavities 132 pass to the shoe block 195as shown in FIG. 23. The openings 140 of the die cavities are sealed bythe shoe block 195 so that powder can flow into the die cavities 132,but will not flow out of the openings 140. The delivery manifold 198directs the purged powder from the cyclone dust separator 199 back intothe die cavities 132. Following this, the die table 114 continues torotate to the fill zone 102.

[0167] An alternate embodiment of the powder recovery system is shown inFIG. 25. This embodiment dispenses with the delivery manifold 198 andshoe block 195. Purged powder is delivered back into the fill zone 102rather than into the die cavity 134. A rotary valve 125 is employed toprevent powder from powder bed 171 from entering the cyclone dustseparator 199. A series of two gate or flap valves (not shown) may alsobe used in place of the rotary valve 125.

[0168] The above systems for purging the powder from the die cavities132 and channels 138 prevents powder build-up and minimizes waste. Ofcourse, this invention in its broadest sense can be practiced withoutsuch a purge zone 110 or a recovery system.

Thermal Cycle Molding Module

[0169] The thermal cycle molding module 200 may function in one ofseveral different ways. It may for example be used to form a shell orcoating over at least part of a dosage form such as a compressed dosageform such as a tablet. It may also be used as stand alone equipment toproduce a molded dosage form per se. Such a coating or dosage form ismade from a flowable material. Preferably, the molding module is used toapply a coating of flowable material to a dosage form. More preferably,the molding module is used to apply a coating of a flowable material toa compressed dosage form made in a compression module of the inventionand transferred via a transfer device also according to the invention.The coating is formed within the molding module by injecting theflowable material, preferably comprising a natural or synthetic polymer,into a mold assembly around the dosage form. The flowable material mayor may not comprise a medicant and appropriate excipients, as desired.Alternately, the molding module may be used to apply a coating offlowable material to a molded dosage form, or other substrate.

[0170] Advantageously, the thermal cycle molding module may be used toapply smooth coatings to substrates that are irregular in topography.The coating thickness achieved with the thermal cycle molding moduletypically ranges from about 100 to about 400 microns. However, therelative standard deviation in the thickness of the coating can be ashigh as about 30%. This means the outside of the coated dosage form canbe made to be highly regular and smooth, even if the substrate below itis not. Once coated, the relative standard deviations in thickness anddiameter of the coated dosage form are typically not greater than about0.35%. Typical coated dosage form thicknesses (shown in FIG. 89 as t)are on the order of about 4 to 10 mm, while typical coated dosage formdiameters (d in FIG. 89) range from about 5 to about 15 mm. It should benoted that subcoats, which are often present in conventional dosageforms, are not necessary on dosage forms coated using the thermal cyclemolding module.

[0171] The thermal cycle molding module 200 preferably cycles betweenhot and cold temperatures during operation. Preferably, the actual moldcavity is held at a temperature generally above the melting point or gelpoint of the flowable material during injection and filling thereof.After the mold cavity is filled its is quickly decreased to below themelting point or gel point of the flowable material thus causing it tosolidify or set. The mold itself is thin like an “egg shell,” andconstructed of a material with a high thermal conductivity, such thatthe mass and geometry of the mold have a negligible effect on the speedat which this thermal cycle is accomplished.

[0172] A significant advantage, then, of the thermal cycle moldingmodule is the dramatically reduced cycle times it affords due to thefact that it can cycle between temperatures that are relatively farapart. The temperature differential between the actual mold cavity andthe flowable material is the major driving force in the solidificationrate of the flowable material. By substantially increasing this ratehigher equipment output can be achieved and subsequent savings inequipment, labor, and plant infrastructure can be realized.

[0173] Moreover, molding of gelatin or similar materials, for examplenon-polymers such as the basic elements, metals, water, and alcohol,have not previously been possible using conventional molding techniquessuch as injection molding. Precise control over the temperature andpressure of such materials, as well as the mold cavity temperature arerequired to assure these materials are sufficiently flowable to fill themold cavity completely. On the other hand, the mold cavity mustsubsequently be cooled enough to assure that the material willeventually solidify. In particular, gelatin, once hydrated, has a veryabrupt transition temperature between the liquid phase and the solid orgel phase. It therefore cannot be characterized as a thermoplasticmaterial. Accordingly, in order to mold gelatin and materials like itthe temperature of the mold must cycle from a first temperature aboveits melting or gel point (to assure that the material will flow andcompletely fill the mold cavity) to a second temperature below itsmelting or gel point (to solidify it).

[0174] In a preferred embodiment of the invention, the flowable materialcomprises gelatin. Gelatin is a natural, thermogelling polymer. It is atasteless and colorless mixture of derived proteins of the albuminousclass which is ordinarily soluble in warm water. Two types ofgelatin—Type A and Type B—are commonly used. Type A gelatin is aderivative of acid-treated raw materials. Type B gelatin is a derivativeof alkali-treated raw materials. The moisture content of gelatin, aswell as its Bloom strength, composition and original gelatin processingconditions, determine its transition temperature between liquid andsolid. Bloom is a standard measure of the strength of a gelatin gel, andis roughly correlated with molecular weight. Bloom is defined as theweight in grams required to move a half-inch diameter plastic plunger 4mm into a 6.67% gelatin gel that has been held at 10° C. for 17 hours.

[0175] In a preferred embodiment wherein the flowable material is anaqueous solution comprising 20% 275 Bloom pork skin gelatin, 20% 250Bloom Bone Gelatin, and approximately 60% water, the mold cavities arecycled between about 35° C., and about 20° C. in about 2 seconds (atotal of 4 seconds per cycle).

[0176] Other preferred flowable materials comprise polymeric substancessuch as polysaccharides, cellulosics, proteins, low and high molecularweight polyethylene glycol (including polyethylene oxide), andmethacrylic acid and methacrylate ester copolymers. Alternative flowablematerials include sucrose-fatty acid esters; fats such as cocoa butter,hydrogenated vegetable oil such as palm kernel oil, cottonseed oil,sunflower oil, and soybean oil; mono- di- and triglycerides,phospholipids, waxes such as Carnauba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax;fat-containing mixtures such as chocolate; sugar in the form on anamorphous glass such as that used to make hard candy forms, sugar in asupersaturated solution such as that used to make fondant forms;carbohydrates such as sugar-alcohols (for example, sorbitol, maltitol,mannitol, xylitol), or thermoplastic starch; and low-moisture polymersolutions such as mixtures of gelatin and other hydrocolloids at watercontents up to about 30%, such as for example those used to make “gummi”confection forms.

[0177] The flowable material may optionally comprise adjuvants orexcipients, in which may comprise up to about 20% by weight of theflowable material. Examples of suitable adjuvants or excipients includeplasticizers, detackifiers, humectants, surfactants, anti-foamingagents, colorants, flavorants, sweeteners, opacifiers, and the like. Inone preferred embodiment, the flowable material comprises less than 5%humectants, or alternately is substantially free of humectants, such asglycerin, sorbitol, maltitol, xylitol, or propylene glycol. Humectantshave traditionally been included in pre-formed films employed inenrobing processes, such as that disclosed in U.S. Pat. No. 5,146,730and U.S. Pat. No. 5,459,983, assigned to Banner Gelatin Products Corp.,in order to ensure adequate flexibility or plasticity and bondability ofthe film during processing. Humectants function by binding water andretaining it in the film. Pre-formed films used in enrobing processescan typically comprise up to 45% water. Disadvantageously, the presenceof humectant prolongs the drying process, and can adversely affect thestability of the finished dosage form.

[0178] Advantageously, drying of the dosage form after it has left thethermal cycle molding module not is required when the moisture contentof the flowable material is less than about 5%.

[0179] Whether coating a dosage form or preparing a dosage form per se,use of the thermal cycling molding module advantageously avoids visibledefects in the surface of the product produced. Known injection moldingprocesses utilize sprues and runners to feed moldable material into themold cavity. This results in product defects such as injector marks,sprue defects, gate defects, and the like. In conventional molds, spruesand runners must be broken off after solidification, leaving a defect atthe edge of the part, and generating scrap. In conventional hot runnermolds, sprues are eliminated, however a defect is produced at theinjection point since the hot runner nozzle must momentarily contact thechilled mold cavity during injection. As the tip of the nozzle retractsit pulls a “tail” with it, which must be broken off. This defect isparticularly objectionable with stringy or sticky materials. Unwanteddefects of this nature would be particularly disadvantageous forswallowable dosage forms, not only from a cosmetic standpoint butfunctionally as well. The sharp and jagged edges would irritate orscratch the mouth, tongue and throat.

[0180] The thermal cycle molding module avoids these problems. Itemploys nozzle systems (referred to herein as valve assemblies) eachcomprising a valve body, valve stem and valve body tip. After injectionof flowable material into the mold cavity, the valve body tip closes themold cavity while comforming seemlessly to the shape of the mold cavity.This technique eliminates visible defects in the molded product and alsoallows a wide range of heretofore unmoldable or difficult to moldmaterials to be used. Moreover, use of the thermal cycle molding moduleaccording to the invention avoids the production of scrap flowablematerial, in that substantially all of the flowable material becomespart of the finished product.

[0181] For convenience, the thermal cycle molding module is describedgenerally herein as it is used to apply a coating to a compressed dosageform. However, FIG. 26A, which is explained further below, depicts anembodiment in which molded dosage forms per se are made using thethermal cycle molding module.

[0182] The thermal cycle molding module 200 generally includes a rotor202, as shown in FIGS. 2 and 3 around which a plurality of mold units204 are disposed. As the rotor 202 revolves, the mold units 204 receivecompressed dosage forms, preferably from a transfer device such astransfer device 300. Next, flowable material is injected into the moldunits to coat the compressed dosage forms. After the compressed dosageforms have been coated, the coating may be further hardened or dried ifrequired. They may be hardened within the mold units or they may betransferred to another device such as a dryer. Continued revolution ofthe rotor 202 repeats the cycle for each mold unit.

[0183]FIG. 29 is a three dimensional view of the thermal cycle moldingmodule 200 as described above. FIG. 30 is a partial view through asection of the thermal cycle molding module as viewed from above showingmultiple mold units 204. FIG. 31 is a section through one of the moldunits 204. The thermal cycle molding module 200 includes at least onereservoir 206 containing the flowable material, as shown in FIG. 4.There may be a single reservoir for each mold unit, one reservoir forall the mold units, or multiple reservoirs that serve multiple moldunits. In a preferred embodiment, flowable material of two differentcolors are used to make the coating, and there are two reservoirs 206,one for each color. The reservoirs 206 may be mounted to the rotor 202such that they rotate with the rotor 202, or be stationary and connectedto the rotor via a rotary union 207 as shown in FIG. 4. The reservoirs206 can be heated to assist the flowable material in flowing. Thetemperature to which the flowable material should be heated of coursedepends on the nature of the flowable material. Any suitable heatingmeans may be used, such as an electric (induction or resistance) heateror fluid heat transfer media. Any suitable tubing 208 may be used toconnect the reservoirs 206 to the mold unit 204. In a preferredembodiment, tubing 208 extends through each of the shafts 213 as shownin FIGS. 30 and 31 to each of the center mold assemblies 212.

[0184] A preferred embodiment of a mold unit 204 is shown in FIG. 31.The mold unit 204 includes a lower retainer 210, an upper mold assembly214, and a center mold assembly 212. Each lower retainer 210, centermold assembly 212, and upper mold assembly 214 are mounted to the rotor202 by any suitable means, including but not limited to mechanicalfasteners. Although FIG. 31 depicts a single mold unit 204 all of theother mold units 204 are similar. The lower retainer 210 and the uppermold assembly 214 are mounted so that they can move vertically withrespect to the center mold assembly 212. The center mold assembly 212 ispreferably rotatably mounted to the rotor 202 such that it may rotate180 degrees.

[0185]FIG. 26A depicts the sequence of steps for making a molded dosageform per se. This employs a simpler embodiment of the thermal cyclemolding module is employed in that the center mold assembly 212 need notrotate. FIG. 26B is a timing diagram showing movement of the mold units204 as the rotor 202 of the thermal molding module completes onerevolution. FIG. 26C is a section through one of the mold units. At thebeginning of the cycle (the rotor at the 0 degree position) the uppermold assembly 214 and the center mold assembly 212 are in the openposition. As the rotor continues to revolve the mold assemblies close toform a mold cavity. After the mold assemblies close, hot flowablematerial is injected from either the upper mold assembly, the centermold assembly, or both into the mold cavity. The temperature of the moldcavity is decreased, and a thermal cycle is completed. After theflowable material hardens, the mold assemblies open. Upon furtherrevolution of the rotor, the finished molded dosage forms are ejectedthus completing one full revolution of the rotor.

[0186]FIG. 27A depicts the sequence of steps for using a secondembodiment of the thermal cycle molding module. Here a coating is formedover a compressed dosage form. In this embodiment, the thermal cyclemolding module coats the first half of a dosage form during revolutionof the rotor 202 between 0 and 180 degrees. The second half of thedosage form is coated during revolution of the rotor between 180 and 360degrees. FIG. 27B is a timing diagram showing movement and rotation ofthe mold units as the rotor completes one revolution. FIG. 27C is asection through one of the mold units showing upper mold assembly 214and center mold assembly 212. Note that the center mold assembly 212 inthis embodiment is capable of rotation about its axis.

[0187] At the beginning of the molding cycle (rotor at the 0 degreeposition) the mold assemblies are in the open position. Center moldassembly 212 has received a compressed dosage form, for example from acompression module according to the invention transferred via a transferdevice also according to the invention. As the rotor continues torevolve, the upper mold assembly 214 closes against center mold assembly212. Next, flowable material is injected into the mold cavity created byunion of the mold assemblies to apply a shell to the first half of thecompressed dosage form. The flowable material is cooled in the moldcavity. The mold assemblies open with the half coated compressed dosageforms remaining in the upper mold assembly 214. Upon further revolutionof the rotor, the center mold assembly rotates 180 degrees. As the rotormoves past 180 degrees the mold assemblies again close and the uncoatedhalf of the compressed dosage form is covered with flowable material. Athermal cycle is completed with setting or hardening of the coating onthe second half of the compressed dosage form. The mold assemblies againopen and the coated compressed dosage form is ejected from the thermalcycle molding module.

[0188]FIG. 28A depicts the sequence of steps for using a preferredembodiment of the thermal cycle molding module to form a coating over acompressed dosage form. In this embodiment, part of a compressed dosageform is coated in the mold cavity created by union of the lower retainerand the center mold assembly 212 during revolution of the rotor between0 and 360 degrees. Simultaneously, the remainder of a second compresseddosage form, the first part of which has already been coated during aprevious revolution of the rotor, is coated in the mold cavity createdby the union of the center mold assembly and the upper mold assembly214. Compressed dosage forms transit through the thermal cycle moldingmodule in a helix, receiving partial coatings during a first fullrotation of the rotor, and then the remainder of their coatings during asecond full rotation of the rotor. Compressed dosage forms are thereforeretained in the thermal cycle molding module for two revolutions of therotor (720 degrees) prior to being ejected as finished products. Thisembodiment of the thermal cycle molding module is advantageous in thatsize of the molding module may be drastically reduced, i.e., to one halfthe diameter of the embodiment shown in FIG. 27A for a given dosage formoutput per rotation. This embodiment of the thermal cycle molding moduleis more economic to fabricate, operate, and house in a high outputmanufacturing plant.

[0189]FIG. 28B is a timing diagram showing movement of the mold unitsand rotation of the center mold assembly as the rotor completes tworevolutions (0 through 720 degrees). FIG. 28C is a section through oneof the mold units. At the beginning of the cycle (0 degrees rotation ofthe rotor) the mold units are in the open position. The center moldassembly 212 contains a partially coated compressed dosage form. Thelower mold assembly 210 receives an uncoated compressed dosage form, forexample from a compression module 100 via a transfer device 300. Uponrotation of the rotor, the center mold assembly 212 rotates 180 degreesabout its axis, which is radial to the rotor. This presents thepartially coated compressed dosage form to the upper mold assembly 214,which is empty. The partially coated compressed dosage form is thendisposed between the upper and center mold assemblies 212, 214. As therotor continues to rotate, the mold units close. The lower retainer 210and center mold assembly 212 create a seal around the uncoatedcompressed dosage form, as shown in FIG. 34.

[0190] Flowable material is injected into the mold cavity createdbetween the lower retainer 210 and the center mold assembly 212 over theuncoated compressed dosage form to cover a part thereof. In a preferredembodiment, the flowable material coats about half of the uncoatedcompressed dosage form, the top half as shown in FIG. 34. Simultaneouslywith the mating of the lower retainer 210 and the center mold assembly212, the center 212 and upper 214 mold assemblies mate to create sealsaround the partially coated compressed dosage form. Flowable material isinjected through the upper mold assembly 214 into the mold cavitycreated by the center mold assembly and the upper mold assembly to coatthe remaining portion of the partially coated compressed dosage form,the top portion as viewed in FIG. 34. The lower retainer 210 and uppermold assembly 214 are mated with the center mold assembly 212simultaneously. Accordingly, when an uncoated compressed dosage form isbeing partially coated between the lower retainer 210 and the centermold assembly 212, the remainder of a partially coated compressed dosageform is being coated between the center 212 and upper mold assemblies214.

[0191] Following this, the lower retainer and the mold assembliesseparate. The fully coated compressed dosage form is retained in theupper mold assembly 214. The partially coated compressed dosage form isretained in the center mold assembly 214, as shown in FIG. 35. The fullycoated compressed dosage form is then ejected from the upper moldassembly 214 as shown schematically in FIG. 35. Following this, anuncoated compressed dosage form is transferred to the lower retainer210, such that the lower retainer 210, center mold assembly 212, andupper mold assembly 214 return to the position of FIG. 32. The processthen repeats itself.

[0192] In the preferred embodiment shown, each mold unit can coat eightcompressed dosage forms. Of course, the mold units can be constructed tocoat any number of compressed dosage forms. Additionally and preferably,the compressed dosage forms are coated with two different coloredflowable materials. Any colors can be used. Alternatively, only aportion of the compressed dosage form may be coated while the remainderis uncoated.

[0193] The molds may also be constructed to impart regular or irregular,continuous or discontinuous, coatings, i.e., of various portions andpatterns, to the dosage forms. For example, dimple patterned coatings,similar to the surface of a golf ball, can be formed using a moldingmodule comprising mold insert having dimple patterns on their surfaces.Alternatively, a circumferential portion of a dosage form can be coatedwith one flowable material and the remaining portions of the dosage formwith another flowable material. Still another example of an irregularcoating is a discontinuous coating comprising holes of uncoated portionsaround the dosage form. For example, the mold insert may have elementscovering portions of the dosage form so that such covered portions arenot coated with the flowable material. Letters or other symbols can bemolded onto the dosage form. Finally, the present molding module allowsfor precise control of coating thickness on a dosage form.

[0194] When used to form a coating on a dosage form, the molding moduleof this invention advantageously dispenses with the need for asubcoating on the dosage form. When conventional compressed dosage formsare coated by processes such as dipping, this generally requires placinga subcoating on the compressed dosage form prior to the dipping step.

[0195] Preferred embodiments of the lower retainer, center mold assemblyand upper mold assembly are described below. These embodiments of thelower retainer, center mold assembly and upper mold assembly are part ofa thermal cycle molding module for applying a coating to a compresseddosage form.

[0196] 1. The Lower Retainer

[0197] The lower retainer 210 is mounted to the rotor 202 as shown inFIG. 31 in any suitable fashion and comprises a plate 216 and a dosageform holder 217. Each dosage form holder can be connected to the plateby any one of a variety of fastening techniques including withoutlimitation snap rings and groves, nuts and bolts, adhesives andmechanical fasteners. Although the cross-section of the lower retainershown in FIGS. 32 through 35 depicts only four dosage form holders 217,the lower retainer preferably has four additional dosage form holdersfor a total of eight. Each dosage form holder includes a flanged outersleeve 218, an elastomeric collet 220, a center support stem 222 and aplurality of flexible fingers 223.

[0198] The configuration of the lower retainer is best understood withreference to FIGS. 36-39. The center support stem 222 establishes thevertical position of the dosage form. The elastomeric collet 220 masksand seals the periphery of the dosage form, as best illustrated in FIGS.36 and 37. Each elastomeric collet 220 mates with a correspondingportion of the center mold assembly 212 in order to create a seal aroundthe dosage form. Although the elastomeric collets can be formed in avariety of shapes and sizes, in a preferred embodiment the elastomericcollets are generally circular and have a corrugated inside surface 221as shown in FIG. 39. The inside surface 221 comprises very small ventholes 224 for air to vent through when the lower retainer 210 is matedwith the center mold assembly 212 and flowable material is injected overthe top portion of the dosage form. The vent holes 224 are relativelysmall so that the flowable material injected over the dosage form fromthe center mold assembly 212 will generally not flow through the ventholes 224.

[0199] As shown in FIGS. 36-39 disposed about the elastomeric collet 220are flexible fingers 223. The flexible fingers 223 are mounted withinthe lower retainer 210 by any suitable means and are attached to thesupport stem 222 to move up and down with the movement of the supportstem 222, as best understood by comparing FIGS. 36 and 37. The flexiblefingers can be coupled to the center support stem by any of a variety offastening techniques.

[0200] In the preferred embodiment shown, the flexible fingers 223 aremetal and spring radially outward when pushed out as shown in FIGS. 37and 38, so that a dosage form can be received by or released from anelastomeric collet 220. The flexible fingers 223 move radially inwardwhen retracted by the center support stem 222 as shown in FIGS. 36 and37 to hold the dosage form within the elastomeric collet 220 firmly.Since the fingers move radially inward they also provide a centeringfunction. The flexible fingers 223 fit between the elastomeric collet220 and the flanged outer sleeve 218 so that when the lower retainer 210is mated with the center mold assembly 212, the dosage form is tightlyheld in place and a seal is created around the dosage form. When anuncoated dosage form is being transferred to the lower retainer 210 or apartially coated dosage form is being transferred from the lowerretainer 210 to the center mold assembly 212, the center support stem222 moves to an upward position as shown in FIG. 36 and the flexiblefingers 223 expand radially outward. Expansion of the flexible fingers223 allows the elastomeric collet 220 to expand as shown in FIG. 38.Radial expansion and contraction of the dosage form holder 217 can beaccomplished by alternative means. For example the flexible fingers 223can be replaced by rigid fingers that pivot on bearings and are actuatedby cam followers. Alternatively linear bearings and plungers arranged ina radial fashion can move or collapse in the radial direction.Mechanisms similar to the shutter of a camera or inflatable bladders inthe shape of an inner tube or torus can also provide similar actions andmovements.

[0201] An actuator assembly 225 that includes in a preferred embodimenta spring 228, a plate 227, a linear bearing 237 and a small cam follower229 as best shown in FIG. 31 can be used to accomplish the verticalmovement required to close or open the dosage form holder 217. The plate227 is mounted to the support stem 222 so that movement of the plate 227in the vertical direction moves the support stem 222. In a preferredembodiment, there is one plate 227 for every eight support stems 222, asshown in FIG. 31. The spring 228 biases the plate 227 and therefore thesupport stems 222 to an upward position as shown in FIG. 36 in which thedosage form is not sealed within the dosage form holder 217. Duringrotation of the rotor 202, the small cam follower 229 rides in small camtrack 215, which causes the plate 227 to move down to seal the dosageform in the dosage form holders 217 as shown in FIG. 37. After molding,the small cam follower 229 along with the spring 228 causes the plate227 to move upward and release the dosage forms.

[0202] Because the flowable material is injected from above the dosageform, as viewed in FIGS. 34 and 37, the edge 226 of the elastomericcollet stops flow of the flowable material. Consequently, only theportion of the dosage form 12 shown in FIG. 36 that is above theelastomeric collet 220 will be coated when the lower retainer 210 andcenter mold assembly 210 are mated. This permits a first flowablematerial to be used to coat one part of the dosage form, and a secondflowable material to coat the remainder of the dosage form-that portionwhich is beneath the elastomeric collet. Although the elastomeric colletis shaped so that about half of the dosage form will be coated at onetime, the elastomeric collet can be of any desired shape to achieve acoating on only a certain portion of the dosage form.

[0203] When two halves of a dosage form are coated with differentflowable materials, the two flowable materials may be made to overlap,or if desired, not to overlap. With the present invention, very precisecontrol of the interface between the two flowable materials on thedosage form is possible. Accordingly, the two flowable materials may bemade flush with each other with substantially no overlap. Or the twoflowable materials may be made with a variety of edges, for example toallow the edges of the flowable materials to interlock.

[0204] Any suitable controls including without limitation mechanical,electronic, hydraulic or pneumatic can be used to move the lowerretainer. In a preferred embodiment the controls are mechanical andinclude a large cam follower 231, large cam track 211 and actuator arm235. The large cam follower 231 rides in large cam track 211 and movesup and down within the large cam track. The actuator arm connects thelarge cam follower to the lower retainer so that movement of the largecam follower up and down causes the lower retainer to move up and down.Thus, as rotor 202 rotates the lower retainer 210 rotates with the rotor202 and the large cam follower 231 moves along the large cam track 211,which is stationary. When at a position to receive dosage forms, thelower retainer 210 is in a down position as shown in FIGS. 36 and 38.After dosage forms have been transferred to the lower retainer 210, thesupport stems 220 move down due to actuation of cam follower 229 andactuator assembly 225 to seal the dosage forms in the lower retainer 210as shown in FIGS. 37 and 39.

[0205] Following this, the large cam follower 231 causes the lowerretainer 210 to move up and mate with the center mold assembly as shownin FIG. 34. Once mated, the dosage form is partially coated in thecenter mold assembly 212. Continued rotation of the rotor 202 causes thelarge cam follower 231 to move down in the large cam track 211, whichthen causes the lower retainer 210 to lower and separate from the centermold assembly 212 back to the position in FIGS. 31 and 35. In addition,rotation of the rotor 202 also causes the actuator 225 to move thesupport stems 222 as described above. The support stem 222 moves torelease the dosage forms just prior to or simultaneously with the lowerretainer moving downward to separate from the center mold assembly 212.Thus, the lower retainer functions to receive dosage forms, hold dosageforms while being partially coated in the center mold assembly 212, andtransfer dosage forms to the center mold assembly after they have beenpartially coated.

[0206] 2. The Center Mold Assembly

[0207] The center mold assembly 212 is rotatably mounted to the rotor202 on an axis that is radial to the rotor. That is, the axis ofrotation of the center mold assembly is perpendicular to the axis ofrotation of the rotor. The arrangement allows the center mold assemblyto rotate 180 degrees (end for end) at a prescribed time while thethermal cycle molding module 200 is simultaneously revolving about itsvertical axis. Preferably, the center mold assembly 212 is mounted sothat it is capable of rotating 180 degrees in either direction.Alternatively, the center mold assembly can be mounted so that itrotates 180 degrees in a first direction and then rotates a further 180degrees. FIG. 30 depicts several center mold assemblies 212 in a planview. All of the center mold assemblies 212 are similarly mounted.

[0208] The center mold assembly comprises a series of back-to-back,identical insert assemblies 230. See FIGS. 32-35, 41 and 42. The centermold assembly 212 rotates partially coated dosage forms from theirdownwardly oriented positions to upwardly oriented positions. Theupwardly pointing portions of the dosage forms, which have been coatedwith flowable material, can now receive the remainder of their coatingsonce the center mold assembly 212 mates with the upper mold assembly214. Also, the insert assemblies previously pointing upward now pointdownward. Thus they are now in a position to mate with the lowerretainer 210 to receive uncoated dosage forms.

[0209] Rotation of the center mold assembly may be accomplished, forexample, using the system shown in FIG. 40. Depicted in FIG. 40 are camfollower carriage 215, cam track ring 285 comprising an upper groove 283and lower groove 281, linkage 279, shaft 213, and rotor 202. As shown,the linkage 279 is geared and shaft 213 has a geared portion, such thatthe shaft 213 will rotate as the linkage 279 moves up and down. Theupper groove 283 and lower groove 281 of the cam track ring 285 areconnected to each other by an “X” or crisscross pattern as shown in FIG.40. This “X” pattern occurs at one location on the cam track ring. Thisallows the cam follower carriage 215 to follow the lower groove 281during a first revolution (360 degrees) of the thermal cycle moldingmodule 200. On a second revolution, the cam follower carriage 215follows the upper groove 283. After 720 degrees of rotation the camfollower carriage 215 switches back to the lower groove 281 and thecycle repeats.

[0210] The groove pattern shown moves the linkage 279 up and down duringrotation of the rotor to control the rotation of the shaft 213 andtherefore the center mold assembly 212. Thus, as the cam followercarriage 215 moves down, the linkage 279 moves down and the shaft 213and center mold assembly 212 rotate counter clockwise as shown in FIG.40. Similarly, when the cam follower carriage 215 moves up, the linkage279 moves up and drives the shaft 213 and center mold assembly 212 torotate clockwise. Each center mold assembly 212 is similarly mounted toa cam follower carriage 215, so that each center mold 212 will similarlyrotate first 180 degrees clockwise at the point where the upper andlower grooves cross, and then upon another revolution of the rotor 202the center molds rotate 180 degrees counterclockwise.

[0211] The cam follower carriage 215 has a pivot point 215D upon whichit is mounted to the linkage 279. Attached to the cam follower carriage215 are three cam followers 215A, 215B, 215C which ride in the groove ofthe cam track ring 285. The use of three cam followers (215A, 215B,215C,) assures that the cam follower carriage 215 follows the correctpath across the “X” crossing point of the cam track ring 285, becausethe gap at the crossing point is shorter than the distance between anytwo cam followers. Upon crossing of the gap two of the three camfollowers remain engaged in the cam track, while the third followercrosses the unsupported region at the crossing point. The path takes theform of a flattened or folded figure eight. The lower groove 281 is thebottom loop of the figure eight and the upper groove 283 forms the toploop.

[0212] Flowable material is preferably heated and cooled in the centermold assembly as follows. Each center mold assembly 212 further includesa valve actuator assembly 232, a dosage form transfer actuator assembly241, and a plurality of manifold plates 234, 236. See FIGS. 43-47. Firstmanifold plates 234 and second manifold plates 236 house insert assembly230, as shown in FIGS. 43 and 46.

[0213] Defined within the first manifold plate 234 is a continuouschannel 238 that defines a coolant/heating flow path, as shown in FIGS.43 and 44. Channel 238 traverses around the insert assembly 230. In apreferred embodiment the coolant/heating fluid is water but any suitableheat transfer fluid may be employed. First manifold plate 234 may alsohave inlet and outlet ports 242 through which the coolant can flowthrough to the channels 238. Ports 242 couple the coolant channels 238to the heat transfer system described below. The first manifold plate234 may be mounted by any suitable means in the center mold assembly212, one of which is by mechanical fasteners.

[0214] Preferably, hot fluid flows through the channels 238 to heat thecenter mold assemblies 212 just prior to and during the injection of theflowable material. Heating can begin prior to or after enclosing thedosage forms within the mold assemblies. Then, simultaneously with orafter injection of the flowable material into the mold assemblies, theheat transfer fluid is preferably switched from hot to cold to solidifythe flowable material.

[0215] The second manifold plate 236 comprises a plurality of holes 248that are aligned with holes 240 in the respective first manifold plate234, so that an insert assembly 230 can be fixed within the holes 240,242. The second manifold plate 236 also comprises channels 250 as shownin FIG. 47. The flowable material flows through the channels 250 to theinsert assembly 230, which directs the flowable material to the dosageforms. Flowable material connector ports 252 may also be included withinthe second manifold plate 236 that allow connection of tubing 208 tochannels 250. Thus, flowable material can be injected from the reservoir206 through the tubing 208, ports 252, channels 250 and to the insertassembly 230.

[0216] As shown in FIGS. 46 and 47, the second manifold plate 236 mayoptionally comprise a heating flow path 236B to warm the insert assembly230 and maintain the flowable material temperature above its meltingpoint. Depending on the type of flowable material used, this heating mayor may not be needed. For example, some flowable materials need to berelatively warm to exhibit good flow properties. Heating flow path 236Bcirculates through the second manifold plate 236 and connects to ports236A. From the ports, tubing (not shown) can be used to connect theheating flow path 236B to a heat exchanger that maintains the heatingfluid warm. Preferably, the heating fluid is water.

[0217] Each insert assembly 230 preferably comprises a stationary part,which includes a center insert 254, and a moveable part, which is inessence a nozzle and comprises a valve body 260, a valve stem 280 andvalve body tip 282, as shown best in FIGS. 41 and 48-50. Although FIGS.48-50 illustrate one nozzle or valve assembly, in a preferred embodimentthere are preferably sixteen such nozzles or valve assemblies per centermold assembly 212, eight facing the upper mold assembly and eight facingthe lower retainer. FIG. 49 depicts the insert assembly 230 in itsclosed position. FIG. 48 shows the insert assembly 230 positioned forinjection of flowable material. FIG. 50 illustrates the insert assembly230 in the dosage form transfer position.

[0218] The center insert 254 may be mounted to the first manifold plate234 by any suitable means, and is preferably sealed with o-rings 262 andgrooves 264 to prevent leakage of flowable material, as shown in FIG.48. The coolant channels 238 are defined between the first manifoldplate 234 and the center insert 254. The center insert 254 isconstructed from a material that has a relatively high thermalconductivity, such as stainless steel, aluminum, berylium-copper,copper, brass, or gold. This ensures that heat can be transferred fromthe heat transfer fluid through the center insert to the flowablematerial. Heating ensures that the flowable material will flow into thecenter mold insert upon injection, and cooling at least partiallyhardens the flowable material. Depending on the type of flowablematerial used, however, heating may not be needed.

[0219] Each center insert 254 comprises a center cavity 266 within it,the surface of which defines the final shape of the dosage form. In apreferred embodiment, center cavity 266 covers about half of a dosageform and is designed such that when mated with the lower retainer 210 orupper mold assembly 214 the dosage form will be covered and sealed.Center cavities 266 can be appropriately shaped and sized based on theparameters of the dosage form. Moreover, the surface of the centercavities may be designed to form coatings having a variety of features,i.e., dimple patterns (similar to a golf ball), holes, symbols includingletters and numbers, or other shapes and figures. Use of the centercavities described herein also permits precise control over thethickness of the molded coating. In particular, with the present thermalcycle molding module 200 coatings having thicknesses of about 0.003 toabout 0.030 inches may be consistently obtained.

[0220] In a preferred embodiment, an air passage 239 is also disposedthrough the first manifold plate 234. See FIG. 45. Compressed air is fedthrough the air passage 239 and used to assist in ejection of the coateddosage form from the center mold assembly 212 to the upper mold assembly214. Although air is preferred for this purpose, the invention is notlimited thereto. An alternative ejector means, such as an ejector pin,may be used. The air can be pressurized to a relatively small pressureand can be provided from air banks or the like that lead to a connectionport in the first manifold plate 234.

[0221] The movable portion of the insert assembly 230 includes the valvebody 260, the valve stem 280, and the valve body tip 282. See FIG. 48.The valve stem 280 is independently moveable. The valve stem 280 andvalve body 260 are slidably mounted within the insert assembly 230. Inthe preferred embodiment shown, a plurality of o-rings 284 and grooves286 seal the moveable portions of the insert assembly to the stationaryportion of the insert assembly. Disposed around the valve stem 280 andthe valve body tip 282 is a flowable material path through whichflowable material traveling through the second manifold plate 236 flowswhen the insert assembly is in the open position (FIG. 48).

[0222] Although the center mold assembly 212 is constructed withidentical insert assemblies 230 on both sides of its rotary axis, eachinsert assembly 230 performs a different function depending on whetherit is oriented in the up or in the down position. When facing down, theinsert assemblies 230 are actuated to inject flowable material to coat afirst portion of a dosage form. The insert assemblies 230 that arefacing up are presenting partially coated dosage forms to the upper moldassembly 214. During this time, the upward facing insert assemblies arein a neutral position. Prior to the molds opening however, the upwardfacing insert assemblies are actuated to allow compressed air to enterthe center cavity 266. This ejects the now completely coated dosageforms from the upward facing insert assemblies. Thus the completeddosage forms remain seated or held in the upper mold assembly 230.

[0223] Advantageously, the center mold assembly is designed to beactuated with just one valve actuator assembly 232 and just one airactuator assembly 241 (FIGS. 41 and 42). The valve actuator assembly 232only actuates the insert assemblies 230 that are facing down, while theair actuator assembly 241 actuates only those insert assemblies 230facing up.

[0224] Downward facing valve stem 280 is spring loaded to the closedposition of FIG. 49 by spring 290. Downward facing valve stem 280 ismoveable between the closed position of FIG. 49 and the open position ofFIG. 48 by valve actuator assembly 232 shown in FIG. 41. In thepreferred embodiment shown, the valve actuator assembly 232 comprises anactuator plate 292 and cam follower 294 mounted thereto. Spring 290 ismounted within the valve stem 280 to spring load the valve stem 280 tothe closed position. An end of the valve stem 280 is mounted within theactuator plate 292 as shown in FIG. 41, so that the valve stem will movewith the actuator plate 292. Actuator plate 292 is mounted to move upand down as viewed in FIG. 41. Cam follower 294 is shown in FIGS. 31 and41. It rides in the cam track 274 disposed around the rotor 202. Camfollower 294 moves up and down according to the profile of cam track 274to move the actuator plate 292 and thereby control movement of thedownward facing valve stem 280.

[0225] Actuator plate 292 moves upward and opens the downward facinginsert assemblies as viewed in FIG. 48 by moving and pulling thedownward facing valve stems 280 against the bias of spring 290 from theposition of FIG. 49 to the position of FIG. 48. Opening of the downwardfacing valve stems ports flowable material to dosage forms disposedbetween the center mold assembly 212 and the lower retainer 210.Following this, cam follower 294 and actuator plate 292 move down torelease the downward facing valve stems 280. Due to the bias of spring290, the downward facing valve stems 280 move to the closed position ofFIG. 49 to stop the flow of flowable material.

[0226] When actuator plate 292 moves up as viewed in FIG. 48, the upwardfacing insert assemblies 230 remain stationary and closed. The upwardfacing valve stems 280 are compressed against spring 290 and do notopen. No flowable material is provided to the upward facing insertassemblies 230. Dosage forms in the upward facing insert assemblies arecoated by the upper mold assembly 214, described below. Similarly, noair is provided to the downward facing insert assemblies because dosageforms are only released from the upward facing insert assemblies.

[0227] After the flowable material has been ported and the downwardfacing insert assemblies 230 return to the position of FIG. 49, camfollowers 246A and 246B and air actuator plate 277 (FIG. 42) initiatemovement of the valve body tip 282 and valve stem 280 of the upwardfacing insert assemblies 230. This provides a path for air through thecenter mold insert. In particular, the upward facing valve body tip 282and valve stem 280 move from the position of FIG. 49 to the position ofFIG. 50 due to movement of cam followers 246A and 246B downward asviewed in FIG. 42. After the application of air, cam followers 246A and246B move downward with the air actuator plate 277, permitting theupward facing insert assemblies 230 to return to the position of FIG.49, ready for another cycle. Air actuator plate 277 does not move thedownward facing insert assemblies 230 during this cycle. They do notreceive air.

[0228] Air actuator plate 277 shown in FIG. 42 controls movement of theupward facing valve body tip 282, valve body 260 and valve stem 280 asfollows. As shown in FIG. 42, pins 282A extend inward with respect tothe center mold assembly 212 and springs 282B are mounted around thepins 282A. The springs 282B press against the upward facing valve bodies260 and are compressed so that the upward facing valve body tip 282 andvalve body 260 are normally in the closed position (FIG. 49). Cam 246Aand air actuator plate 277 move downward to compress the springs 282Aand push the upward facing valve body 260 and valve body tip 282 againstthe bias of the springs 282B to the opened position (FIG. 50).

[0229]FIG. 50 depicts an upward facing insert assembly 230 in thetransfer position. In this position, the upward facing valve stem 280and valve body tip 282 are withdrawn. The upward facing valve stem 280rests against the upward facing valve body tip 282 to stop the flow offlowable material. With the valve body tip 282 withdrawn, however, airfrom can flow to the mold.

[0230] After the dosage forms have been transferred from the center moldassembly, the air actuator plate 277 returns up to release the upwardfacing valve body 260, valve body tip 282 and valve stem 280 to theclosed position of FIG. 49.

[0231] 3. The Upper Mold Assembly

[0232] The upper mold assembly 214, which is shown in FIGS. 51-54, issimilar in construction to half of the center mold assembly 212. Likethe center mold assembly 212, the upper mold assembly 214 directsflowable material to at least partially coat a dosage form. Inparticular, the upper mold assembly 214 has a plurality of upper insertassemblies 296 (eight in the preferred embodiment) that mate withcorresponding insert assemblies 230.

[0233] Although the upper mold assembly is similar to the center moldassembly, the upper mold assembly does not rotate. Rather, the uppermold assembly 214 moves vertically up and down to mate with the centermold assembly via suitable controls as best understood by comparingFIGS. 32-35. Preferably, cam follower 299, cam track 298, and connectorarm 293 (FIG. 51) are used to control the movement of the upper moldassembly 214. Small cam follower 289 and small cam track 288 controlupper actuator plate 291. Cam follower 299, cam track 298, small camfollower 289, and small cam track 288 are similar in construction to thecorresponding elements of the lower retainer 210.

[0234] The upper mold assembly 214 moves during rotation of the rotor202 via cam follower 299 to mate with the center mold assembly 212 asshown in FIGS. 32-35 and at least partially coat a dosage form. Afterthis, the cam follower 299 separates the upper mold assembly 214 fromthe center mold assembly 212 so that the finished, fully coated dosageform can be ejected and transferred from the thermal cycle moldingmodule as shown in FIG. 35.

[0235] The upper mold assembly 214 comprises an upper second manifoldplate 251 that ports flowable material to upper insert assemblies 296and is similar in construction to the second manifold plate 236 of thecenter mold assembly 212. An upper first manifold plate 253 providescooling/heating to the upper insert assemblies 296 and is similar inconstruction to the first manifold plate 234 of the center mold assembly212.

[0236] A seal around each dosage form is preferably created by contactbetween the upward facing insert assembly 230 of the center moldassembly 212 and the upper insert assembly 296 of the upper moldassembly 214, as best understood with reference to FIGS. 48-50. An upperinsert assembly 296 is depicted in FIGS. 52-54 in the closed, open andeject positions, respectively. Similar to the insert assemblies 230,each upper insert assembly 296 includes a stationary portion thatincludes an upper insert 265 and a upper flanged insert 258 and amoveable portion that is basically a nozzle. The latter comprises anupper valve body 273, upper valve stem 297 and upper valve body tip 295.The upper valve stem 297 is moveable between open and closed positionsto control flow of the flowable material to the dosage form. The uppervalve body, upper valve stem and upper valve body tip define the flowpath for the flowable material.

[0237] Each upper cavity 272 is appropriately sized so that the flowablematerial can flow over the dosage form and provide a coating of thedesired thickness. Similar to the center cavity 266 of the center insert254, the upper cavity 272 of the upper insert 265 can be of any desiredshape and size or be provided with a surface pattern (such as dimples,letters, numbers, etc.).

[0238] One difference between the upper insert assembly 296 and theinsert assembly 230 is that the upper valve body tip 295 forms part ofthe seal around the dosage form as shown in FIGS. 52-54 and movesoutward rather than inward to eject a dosage form after it has beenfully coated. FIG. 54 depicts the upper valve body tip 295 positioned toeject a dosage form. FIG. 52 depicts the upper valve body tip 295positioned to receive a dosage form.

[0239] An upper valve actuator 275 that includes an upper actuator plate291, linkage 291B and cam follower 289 as shown in FIG. 51 actuate theupper insert assembly 296. In other embodiments, electronic or othermechanical controls can be used. The linkage 291B couples cam follower289 to the upper actuator plate 291. The upper actuator plate 291 has aportion 291D that extends beneath a plunger so that when the upperactuator plate 291 moves up (FIG. 53) it pulls on valve stem 297. Upperactuator plate 291 also rests on top of upper valve stem 297 so thatwhen the upper actuator plate 291 moves down, the plunger and the uppervalve stem 297 are pushed down (FIG. 54).

[0240] As the rotor 202 rotates, cam follower 289, riding in cam track298, moves up, causing the upper actuator plate 291 to rise and pullupper valve stem 297 against the bias of spring 269 and hence move itfrom the closed position of FIG. 52 to the open position of FIG. 53.After this, cam follower 289 moves down and causes upper actuator plate291 to move upper valve stem 297 to the closed position of FIG. 52.

[0241] Next, cam follower 289 moves down and causes upper actuator plate291 to move further down. When upper actuator plate 291 moves down, itdepresses upper valve stem 297, which pushes upper valve body 273 andupper valve body tip 295 against the bias of spring 271. Upper valvebody tip 295 thus assumes the position of FIG. 54 to eject a dosageform. In addition, as upper valve body tip 295 moves down air is portedaround it from the compressed air path 267. As with the center moldassembly, compressed air in the upper mold assembly ensures that thecoated dosage form does not stick to the upper insert 265 when it isejected.

[0242] After the coated dosage form is ejected, it may be sent to atransfer device, dryer, or other mechanism. Following this, cam follower289 and upper actuator plate 291 move back up. This in turn moves uppervalve stem 297 and upper valve body tip 295 back to the position of FIG.52 due to the bias of spring 271.

[0243] Similar to the center mold assembly, heated heat transfer fluidis directed through the upper first manifold plate 253 and upper insertassembly 296 to heat them during injection of the flowable material.Chilled heat transfer fluid is directed through the upper first manifoldplate 253 and upper insert assembly 296 after the flowable material hasbeen injected to harden it. In addition, warm heat transfer fluid can besent through the upper second manifold plate 251 constantly to heat theflowable material above its melting point.

[0244] 4. Temperature Control and Energy Recovery System

[0245] Preferably, the center and upper mold assemblies 212, 214 of thethermal cycle molding module are hot, i.e., above the melting point ofthe flowable material, when the flowable material is injected into them.This assists the flowable material in flowing. The mold assemblies arethen preferably cooled, i.e., to below the melting or settingtemperature of the flowable material, rather quickly to harden theflowable material.

[0246] In light of this cycle, a heat sink, a heat source and atemperature control system are preferably provided to change thetemperature of the molds. Examples of heat sinks include but are notlimited to chilled air, Ranque Effect cooling, and Peltier effectdevices. Examples of heat sources include electric heaters, steam,forced hot air, Joule Thomson effect, ranque effect, ultrasonic, andmicrowave heating. In a preferred embodiment, a heat transfer fluid suchas water or oil is used to transfer heat, while electric immersionheaters provide the heat source for the heat transfer fluid. Preferably,electrically powered freon chillers provide the heat sink for the heattransfer fluid.

[0247]FIGS. 55 and 56 depict the preferred temperature control system600 for the center mold assemblies and upper mold assemblies. Althoughonly one mold assembly 214/212 is depicted, all mold assemblies areconnected to the temperature control system in a similar fashion.Preferably, the temperature control system 600 includes a tubing system606 and valves 620 to 623. Tubing system 606 includes a cold loop 608for cooling mold assembly 214/212, and a hot loop 609 for heating them.Both loops share a common flow passageway between “T” fitting 603 and“T” fitting 605. Defined within the common flow passageway between “T”fitting 603 and “T” fitting 605 is a flow path in the mold assembly214/212. Valves 620 to 623, which may be solenoid or mechanicallyoperated, control the flow of cool or heated heat transfer fluid throughthe mold assembly 214/211. The system may also include a heater 610,which heats the hot loop, and a chiller 612, which provides a chilledfluid source for the cold loop. Outlet ports 612A and inlet ports 612Bof the chiller and outlet ports 610A and inlet ports 610B of the heatercan be connected to multiple molds, so that a single chiller and asingle heater can support all of the upper molds 214 and center molds212.

[0248] Valves 620 to 623 are initially in the position of FIG. 55.Valves 621 and 623 of the hot loop 609 are open so that hot heattransfer fluid can flow and circulate through the mold assembly 214/212.In contrast, the valves of the cold loop 620 and 622 are closed so thatcoolant cannot flow through that loop. After flowable material has beeninjected into the hot mold assembly 214/212, the cycle is switched tothe cooling mode by closing solenoid valves 620 and 622 of the hot loopand opening valves 603 and 605 of the cold loop 608 (see FIG. 56). Thisblocks the flow of hot heat transfer fluid to the molds assembly214/212, and starts the flow of chilled heat transfer fluidtherethrough. Preferably, the center mold assembly 212 and the uppermold assembly 214 are capable of cycling in the temperature range ofabout 0 to about 100° C. in about 1 seconds to 30 seconds. In thepreferred embodiment using gelatin at 60% moisture content, the centerand upper mold assemblies 212, 214 cycle between about 35° C. and 20° C.in about 2 seconds.

[0249] The cold and hot heat transfer fluid thus flows in the commonflow passageway between “T” fittings 603 and 605. When the valves switchfrom the heating mode to the cooling mode, the volume of hot heattransfer fluid enclosed within the common flow passageway is transferredto the cold side of the system. Conversely, hot heat transfer fluidtrapped in the common flow passageway is transferred into the cold loopwhen the valves switch to the heating mode.

[0250] Although the volume of fluid in the common flow passageway isrelatively small, and the cost of energy to heat and chill this volumeof fluid is not unreasonable for a commercial process, a more preferred,energy efficient, and cost effective temperature control system isdepicted in FIGS. 57-59. This preferred temperature control system 600includes the following components additional to those described above: afluid reservoir 630, a moveable piston 604 bisecting the fluidreservoir, and valves 626 and 627. The fluid reservoir can be replacedwith two collapsible bladders (hot and cold), thus eliminating the needfor the piston 604. For ease of description, however, the reservoir andpiston embodiment is described herein. Valves 620, 621,622,623,626 and627, which may be solenoid or mechanically operated, control the flow ofcool or hot heat transfer fluid through the system. Each mold assembly214/212 has its own fluid reservoir 630, piston 604, and valves 620,621,622,623,626 and 627. Initially, the valves are in the position ofFIG. 57. Valves 620, 622, and 626 of the cold loop are open so that coolheat transfer fluid can flow to the mold assembly 214/212. In contrast,the valves of the hot loop 621, 623,627 are closed so that hot heattransfer fluid cannot flow through that loop. The piston 604 is forcedto the cold loop side by the position of the valves 626,622,623, and627.

[0251] When the system switches to heating mode the solenoid valves,which are controlled by an electronic signal or by mechanical (cam)actuation, close or open as shown in FIG. 58. Valves 620, 626, and 623close and valves 621, 622, and 627 open. This blocks the flow of coolheat transfer fluid from the cold loop to the mold assembly 214/212 andstarts the flow of hot heat transfer fluid through the mold assembly214/212. This permits the hot heat transfer fluid to shift piston 604 tothe position shown in FIG. 58. When piston 604 is in the far rightposition it is generally configured to contain a volume of liquid equalto fluid enclosed within the passageway between “T” fittings 603 and605. This volume is tunable by adjusting when the valves open and close,or by adjusting the volume of the fluid reservoir 630. When piston 604reaches its preselected rightmost position (FIG. 59) valves 622, 626,and 620 close and valves 621, 623, and 627 open. The fluid contained inthe fluid reservoir to the left of piston 604 is cold. Fluid to theright of piston 604 is hot and most of this hot fluid has been evacuatedfrom the cylinder. The heating mode of the system is now in progress inFIG. 59. When the system switches to cooling mode, piston 604 moves inthe opposite direction (to the left) and fills with hot fluid thusreversing the process just described. By preventing or minimizing hotheat transfer fluid from entering the chilled side and by preventingcold heat transfer fluid from entering the hot side, energy losses areminimized and the system is maximally efficient.

[0252] FIGS. 60-62 depict a particularly preferred embodiment of the thetemperature control system incorporating an automatic valve system 650.The automatic valve system 650 directs heat transfer fluid to energyrecovery bladders 651 and 652. The automatic valve system 650 replacesvalves 622 and 623 of the system described in FIGS. 57-59. Connectingenergy recovery bladders together is connection rod 653. Slidablymounted to the connection rod 653 is valve slide 654.

[0253] Operation of the automatic valve system 650 is best understood bycomparing FIGS. 60 through 62. In FIG. 60 cold heat transfer fluid iscirculating and hot heat transfer fluid is not. The energy recoverybladders are shifted to the right most position with hot heat transferfluid filling bladder 652. Valve slide 654 is seated in its right mostposition by a flanged portion 653A of connection rod 653 allowing fluidto pass to the left.

[0254] In FIG. 61, the temperature control system has just switched fromcooling mode to heating mode by switching valves 620 and 626 from theiropen to closed positions. Valves 621 and 627 have switched from closedto open positions, allowing hot heat transfer fluid to begin flowingaround loop 609. The pressure from the fluid in loop 609 forces energyrecovery bladder 651 to fill and move to the left as shown in FIG. 61.Simultaneously, energy recovery bladder 652 empties and moves to leftdue to the linking of the bladders by connection rod 653. The valveslide 654 functions as a check valve and remains seated to the right dueto pressure against its left face. As bladders 651 and 652 continue tomove to the left, flanged portion 653B of connection rod 653 makescontact with the right face of valve slide 654, unseating it andshifting it to the left most position shown in FIG. 62. The temperaturecontrol system is now in the heating mode. When the temperature controlsystem switches back from heating to cooling mode the cycle repeats andthe bladders 651 and 652 move to the right.

[0255] As described above, valves 620 through 623 of the temperaturecontrol system can be of various designs known in art, such as spool,plug, ball, or pinch valves. These valves can be actuated by suitablemeans such as air, electrical solenoids, or by mechanical means such ascam tracks and cam followers. In a preferred embodiment, the valves arepinch valves and are actuated by mechanical cam tracks and cam followersas the thermal cycle molding module rotates. Known pinch valves arerelatively simple devices comprising a flexible section of tubing and amechanism that produces a pinching or squeezing action on the tubing.This tubing is compressed or “pinched” to block fluid flow therethrough.Release of the tubing allows fluid to flow. Accordingly, the pinch valvefunctions as a two-way valve.

[0256] The pinch valves of the present temperature control systemutilize a rotary design to “pinch” and “unpinch” flexible tubing. Asdescribed above, the center mold assembly rotates clockwise and thencounterclockwise over an arc of 180 degrees. Feeding the center moldassembly are eight tubes 606 that supply heat transfer fluid (two supplyand two return lines for each mold assembly). FIGS. 63-65 depict arotary pinch valve assembly 660 of the invention. The rotary pinch valveassembly 660 comprises a valve anvil 661 fixed to shaft 662. Shaft 662is attached to center mold assembly 212 (not shown) so that it canrotate about the same axis. Rotatably mounted to shaft 662 is valvepinch arm 663A. A similar valve pinch arm 663B is also rotatably mountedto shaft 662 and is free to move independently of valve pinch arm 663A.Actuating the valve pinch arms are valve actuators 665A and 665B, whichmove cam follows 666A and 666B in the vertical direction. The verticalrise and fall of actuators 665A and 665B causes corresponding movementsof cam followers 666A and 666B, which imparts a rotational movement tovalve pinch arms 663A and 663B via gears 667A and 667B, which arerotatably mounted to valve anvil 661. Gears 667A and 667B reduce oramplify the rotational movement of the valve pinch arms 663A and 663B byan amount proportional to the gear ratio. Although gears 667A and 667Bare used in the preferred embodiment described here, in otherembodiments they can be dispensed with. Rotational movement of the valvepinch arms can be imparted directly by cam followers and actuators.

[0257] The counter clockwise rotation of valve pinch arms 663A and 663Babout shaft 661 causes tubes 606B to be squeezed closed and tubes 606Ato remain open. Conversely, clockwise rotation of valve pinch arms 663Aand 663B about shaft 661 causes tubes 606A to be squeezed closed andtubes 606B to remain open. The position of the valves (open or closed)depends on whether the orientation of center mold assembly 212 is up ordown. It is also a requirement that the position of the valves remainunchanged (or controlled) as the center mold assembly makes its 180degree rotation. As shown in FIG. 64, the circular cam track 669 allowscam followers 666A and 666B to remain in their fully actuated positionswhile the rotary pinch valve assembly 660 rotates clockwise and counterclockwise 180 degrees. Cam followers 666A and 666B can transit eitherthe inner surface or outer surface of the circular cam track 669 asshown in FIG. 64.

Transfer Device

[0258] 1. Structure of the Transfer Device

[0259] Known tablet presses use a simple stationary “take-off” bar toremove and eject tablets from the machine. Since the turrets of thesemachines rotate at fairly high speeds (up to 120 rpm), the impact forceson the tablets as they hit the stationary take-off bar are verysignificant. Dosage forms produced on these machines must therefore beformulated to posses very high mechanical strength and have very lowfriability just to survive the manufacturing process.

[0260] In contrast with prior art devices, the present transfer deviceis capable of handling dosage forms having a higher degree offriability, preferably containing little or no conventional binders.Thus, a preferred formulation for use with present invention comprisesone or more medicants, disintegrants, and fillers, but is substantiallyfree of binders. Dosage forms having a very high degree of softness andfragility may be transferred from any one of the operating modules ofthe invention as a finished product using the transfer device, ortransferred from one operating module to another for further processing.

[0261] The present transfer device is a rotating device, as shown inFIGS. 3 and 68. It comprises a plurality of transfer units 304. It ispreferably used for transferring dosage forms or inserts within acontinuous process of the invention comprising one or more operatingmodules, i.e., from one operating module to another. For example, dosageforms may be transferred from a compression module 100 to a thermalcycle molding module 200, or from a thermal setting molding module 400to a compression module 100. Alternatively, the transfer device can beused to transfer dosage forms or other medicinal or non-medicinalproducts between the devices used to make such products, or to dischargefragile products from such machines.

[0262] Transfer devices 300 and 700 are substantially identical inconstruction. For convenience, transfer device 300 will be described indetail below. Each of the transfer units 304 are coupled to a flexibleconveying means, shown here as a belt 312 (FIGS. 68 and 69), which maybe made of any suitable material, one example of which is a compositeconsisting of a polyurethane toothed belt with reinforcing cords ofpolyester or poly-paraphenylene terephthalamide (Kevlar®, E. I. duPontde Nemours and Company, Wilmington, Del.). The belt runs around theinner periphery of the device 300. The transfer units 304 are attachedto the belt 312 as described below.

[0263] The transfer device can take any of a variety of suitable shapes.However, when used to transfer dosage forms or inserts between operatingmodules of the present invention, transfer device is preferablygenerally dog bone shaped so that it can accurately conform to the pitchradii of two circular modules, enabling a precision transfer.

[0264] The transfer device can be driven to rotate by any suitable powersource such as an electric motor. In a preferred embodiment, thetransfer device is linked to operating modules of the invention and isdriven by mechanical means through a gearbox which is connected to themain drive motor 50. In this configuration the velocity and positions ofthe individual transfer units of the transfer device can be synchronizedwith the operating modules. In a preferred embodiment the drive trainincludes a drive pulley 309 and an idler pulley 311 which are in thepreferred embodiment disposed inside of the transfer device 300. Thedrive shaft 307 connects the main drive train of the overall linkedsystem to the drive pulley 309 of the transfer device. The drive shaft307 drives the drive pulley 309 to rotate as shown in FIGS. 3 and 68.The drive pulley 309 has teeth 309A that engage teeth 308 disposed onthe interior of belt 312, which in turn rotates the transfer device. Theidler pulley 311 has teeth 311A that engage belt 312, which causes theidler to rotate with the belt 312. Other flexible drive systems, such aschains, linked belts, metal belts, and the like can be used to conveythe transfer units 304 of the transfer device 300.

[0265] As shown in FIGS. 68 and 69, attached to the outer periphery ofthe transfer device 300 is a dog bone shaped cam track 310 whichprecisely determines the path for the belt and the transfer units. Theradii of the cam track 310, the pitch distance between the transferunits 304, the pitch of the toothed belt 312, and the gear ratio betweenthe drive pulley 309 and the main drive of the linked system are allselected such that the transfer device is precisely aligned with theoperating modules linked to it. As each operating module rotates, thetransfer device remains synchronized and phased with each, such that aprecise and controlled transfer from one operating module to another isachieved. The velocity and position of the transfer unit 304 is matchedto the velocity and position of the operating module along the concaveportions of the cam track. Transfers are accomplished along this arclength. The longer the length of the arc, the greater the time availableto complete a transfer. Riding in cam track 310 are cam followers 305suitably mounted to the transfer units (FIG. 70).

[0266] In a preferred embodiment of this invention, both the drivepulley 309 and the idler pulley 311 are driven. FIGS. 68 and 69 depict atoothed pulley 350, a second toothed pulley 351 and a toothed belt 352.Pulleys 350, 351 and belt 352 connect the rotation of the drive pulley309 with the rotation of the idler pulley 311. This advantageouslyeliminates any slack side condition in the belt. Linking of pulleys 309and 311 could also be accomplished using gears, gear boxes, line shafts,chains and sprockets or by synchronized electric motors.

[0267] A preferred transfer unit 304 is depicted in FIGS. 70-75, andgenerally includes a pair of plunger shafts 320, one or preferably morethan one cam follower 322, a plurality of bearings 324 to retain theplunger shafts 320, a spring 326, a plate 328 that secures the plungershafts 320 to cam follower 322 thereby controlling their movement, and aretainer 330. Preferably, each transfer unit 304 is attached to flexibleconveying means 312 in a cantilever configuration so that retainers 330are cantilevered over the path of the dosage forms. This allows formultiple rows of retainers in the transfer unit and keeps contaminationby dirty mechanical parts away from the dosage form and its subcomponents. Moreover, it allows the flexible conveying means to contactclosely the operating modules to which it is connected, thereby allowingfor a smooth transfer pathway.

[0268] Retainers 330 are preferably flexible and constructed from anelastomeric material so that when no dosage form is inserted into theretainer 330, the retainer 330 generally points radially inward as shownin FIG. 71. When a dosage form is pushed into the retainer 330, theretainer 330 flexes upward as shown in FIG. 72. The dosage form passesthe retainer 330 and releases it so that the retainer supports thedosage form in the transfer unit from below. A dosage form is ejectedfrom a transfer unit by pushing down on the dosage form, thereby flexingthe retainer and permitting the dosage form to be pushed out. Oncereleased, the retainer 330 flexes back to its radially inward positionso that it can receive another dosage form. In a preferred embodiment,the retainer 330 is circular and includes segmented fingers ofelastomeric material as shown in FIG. 71, but it need not be soconstructed. It need only be flexible enough to flex, hold the dosageform, and release the dosage form. Retainer 330 extends radially inwarda distance such that when the dosage form is pushed past it, it holdsthe dosage form in place until it is ejected by the plunger shafts 320,as described below.

[0269] Cam follower 322 is disposed towards the top of the transfer unit304. It is mounted so that it can move up and down as shown in FIGS.70-74. Plate 328 is coupled to cam follower 322. Spring 326 is connectedto transfer unit 304 and biases the plate 328 and cam follower 322 to anupper position. Plate 328 is also coupled to each plunger shaft 320, sothat movement of the plate 328 will cause movement of the plunger shafts320.

[0270] Each plunger shaft 320 is mounted within the transfer unit 304 bya plurality of bearings 324 that permit vertical movement of the plungershafts 320. The plunger shafts 320 are mounted so that one end of eachplunger shaft 320 can move into the respective space in which a dosageform is retained to eject it from the retainer 330, as shown in FIG. 74.As described below, the plunger shafts 320 move in response to movementof the plate 328 and the roller bearing 322 to eject dosage forms fromthe transfer unit 304. The plunger shafts 320 and bearings 324 may bemade of any suitable material.

[0271] 2. Operation of the Transfer Device

[0272] Operation of the transfer device is best understood withreference to FIGS. 3 and 70-75. A description of the operation of onetransfer unit 304 is provided, but it will be understood that the othertransfer units 304 operate in a similar fashion. Moreover, operation isdescribed with respect to transfer of a dosage form from a compressionmodule to a thermal cycle molding module, however, as stated above,transfer may be accomplished between any two operating modules or otherdevices. For example, FIG. 76 depicts a transfer device 700 transferringan insert from a thermal setting mold module to a compression module.The sole differences between transfer devices 300 and 700 are thegeometry of the transferred object and the geometry of the transfer unitholders.

[0273] The transfer device operates as follows. The transfer unit 304passes by the die table 114 of the compression module 100 and the tworetainers 330 of the transfer unit 304 become aligned with die cavities132 that are on a radial line, as shown on the left of FIG. 75. At thepoint of alignment, lower punch 120 moves upward in unison with plungershafts 320 due to the cam tracks as described above. A dosage form 12 isejected into the retainers 330 of the transfer unit 304 as shown inFIGS. 72, 73 and 75. The dosage form flexes the retainer 330 until itmoves past the retainer 330 and is held in the transfer unit 304 by theretainer 330. Since the plunger shafts and lower punches capture thedosage form in a confined space with minimal clearance, the dosage formcan not rotate or move randomly, which could jam this or subsequentapparatus. The dosage form is therefore fully controlled before, during,and after transfer. Rotation of the transfer device 300 and die table114 of the compression module 100 are synchronized so that transferunits 304 will continually pass above the die cavities 132 and dosageforms will be continuously transferred to the transfer units 304.

[0274] Further rotation of the transfer device 300 by the drive pulleycauses the belt 312 and its attached transfer units 304 to rotate.Eventually, the transfer units 304 containing the dosage forms reach thelower retainer 210 of the thermal cycle molding module 200, as shown inFIGS. 3 and 75. Cam 310 is disposed between the center mold assembly 212and the lower retainer 210. The lower retainer 210 passes just beneaththe transfer units 304. Thus, the transfer units 304 become aligned withtwo of the elastomeric collets 220 in the lower retainer. As thetransfer unit 304 moves along cam track 310, cam track 310 pushes on thecam follower 322, which pushes on plate 328. Plate 328 moves the plungershafts 320, which in turn move down and contact the dosage forms. Thiscontact pushes the dosage forms past the elastomeric collets, and thedosage forms move out and into the elastomeric collets 220. Lowerretainer 210 and the transfer device 300 are rotating at speeds thatpermit the dosage forms to be continuously transferred from the transferunits 304 to the lower retainers 210. As the retainers 330 move past thethermal cycle molding module, plunger shafts 320 return to theiroriginal upward position.

[0275] 3. Rotational Transfer Device

[0276] In a preferred alternate embodiment of this invention, arotational transfer device is employed. Such a device is useful forhandling dosage forms that must be both transferred from one piece ofequipment and reoriented, for instance from a horizontal position to avertical position, or vice versa. For example, two color gelcaps,elongated dosage forms in which the boundary between colors lies alongthe short axis of the dosage form (see FIG. 81), must be compressedhorizontally along their long axis, but coated in a vertical position.Accordingly, gelcaps compressed in the present compression module 100and coated the thermal molding module 200 must be both transferred fromthe compression module and reoriented into a vertical position.

[0277] FIGS. 77-81 depict a preferred rotational transfer device 600,which is similar in construction to the transfer devices 300 and 700.Like transfer devices 300 and 700 the rotational transfer device 600 isa rotating device as shown in FIGS. 77 and 79. It comprises a pluralityof rotatable transfer units 602 coupled to a toothed belt 604. Riding inthe shaped cam track 606 are cam followers 607 suitably mounted to thetransfer units 602.

[0278] Each transfer unit 602 consists of a dosage form holder 608rotatably mounted in a housing. Connected to the housing is a shaft 616(FIG. 80). Ejector pin assembly 612 slides on bearings 614 along shaft616 and its vertical movement is controlled by cam follower 618 and camtrack 620. Within the housing is gear 622, which is attached to theshaft of the dosage form holder 608 and gear 623 which is attached tothe shaft of the actuator arm 624. Attached to actuator arm 624 is camfollower 626 which rides in cam track 628. The vertical rise and fall ofcam track 628 causes a corresponding movement of cam follower 626 whichimparts a rotational movement to actuator arm 624. As the actuator armrotates, gears 622 and 623 amplify this rotation causing dosage formholder 608 to rotate by an amount proportional to the gear ratio. Thegear arrangement and offset design of the actuator arm keep the transferunits symmetrical about the vertical axis between cam followers 607.This symmetry of construction is required to assure proper tracking ofcam followers 618 and 626 and dosage form holder 608 as they transitthrough the various concave and convex radii of the rotational transferdevice 600.

[0279] One sequence of operations of the rotational transfer device 600is depicted in FIGS. 79-81. Elongated dosage forms (caplet 690) arecompressed horizontally in the compression module 100 and aretransferred through flexible retainers 630 into the dosage form holder608, which is also in a horizontal orientation (FIG. 80, FIGS. 81A, 81B,and 81E). Upon further transit through shaped cam track 606 the dosageform holder 608 rotates 90 degrees to a vertical orientation due tomotion of cam follower 626 within cam track 628 (FIGS. 81C and 81F).Upon reaching lower retainer 210 of thermal cycle molding module 200,caplet 690 is transferred through a second flexible retainer 630B viathe vertical movement of ejector pin assembly 612. Ejector pin assembly612 enters through holes 608A in dosage form holder 608 to evacuate thechamber 680 that holds caplet 690 (FIGS. 81C and F and FIGS. 81D and G).Caplet 690 is now transferred to the lower retainer 210 and upon furthertransit through the shaped cam track 606, the dosage form holder 608rotates 90 degrees, returning to its horizontal position to begin thecycle over again (FIG. 79).

Hardening Apparatus

[0280] Dosage forms that have been coated with flowable material in thethermal cycle molding module are relatively hard compared with dosageforms that have coated using conventional dipping processes. Thus, theamount of drying needed after molding a coating onto a dosage form usingthe thermal cycle molding module is substantially less than thatrequired with known dipping processes. Nevertheless, they may stillrequire hardening, depending upon the nature of the flowable material.

[0281] Preferably, dosage forms coated in the thermal cycle moldingmodule are relatively hard so that they can be tumble hardenedrelatively quickly. Alternatively, an air dryer may be used. Anysuitable dryers may be used. A variety are generally understood in theart.

Thermal Setting Molding Module

[0282] The thermal setting molding module may be used to make dosageforms per se, coatings, inserts for dosage forms, and the like from astarting material in flowable form. The thermal setting molding modulemay be used as part of the overall system 20 of the invention (i.e.,linked to other modules) or as a stand alone unit.

[0283] The thermal setting molding module 400 is a rotary apparatuscomprising multiple hot injection nozzles and cold molding chambers.Each molding chamber has its own nozzle. Advantageously, the volume ofthe molding chambers is adjustable.

[0284] In a preferred embodiment of the invention, the thermal settingmolding module is used to make inserts for dosage forms. The inserts canbe made in any shape or size. For instance, irregularly shaped inserts(or dosage forms per se) can be made, that is shapes having no more thanone axis of symmetry. Generally however, cylindrically shaped insertsare desired.

[0285] The inserts are formed by injecting a starting material inflowable form into the molding chamber. The starting material preferablycomprises an medicant and a thermal setting material at a temperatureabove the melting-point of the thermal setting material but below thedecomposition temperature of the medicant. The starting material iscooled and solidifies in the molding chamber into a shaped pellet (i.e.,having the shape of the mold). Injection and molding of the insertspreferably occurs as the thermal setting molding module 400 rotates. Ina particularly preferred embodiment of the invention, a transfer device700 (as described above) transfers shaped pellets from the thermalsetting molding module to a compression module 100 (also describedabove) as generally shown in FIG. 2, to embed the shaped pellets into avolume of powder before such powder is compressed into a dosage form inthe compression module.

[0286] The starting material must be in flowable form. For example, itmay comprise solid particles suspended in a molten matrix, for example apolymer matrix. The starting material may be completely molten or in theform of a paste. The starting material may comprise a medicant dissolvedin a molten material. Alternatively, the starting material may be madeby dissolving a solid in a solvent, which solvent is then evaporatedfrom the starting material after it has been molded.

[0287] The starting material may comprise any edible material which isdesirable to incorporate into a shaped form, including medicants,nutritionals, vitamins, minerals, flavors, sweeteners, and the like.Preferably, the starting material comprises a medicant and a thermalsetting material. The thermal setting material may be any ediblematerial that is flowable at a temperature between about 37 and about120° C., and that is a solid at a temperature between about 0 and about35° C. Preferred thermal getting materials include water-solublepolymers such as polyalkylene glycols, polyethylene oxides andderivatives, and sucrose esters; fats such as cocoa butter, hydrogenatedvegetable oil such as palm kernel oil, cottonseed oil, sunflower oil,and soybean oil; mono- di- and triglycerides, phospholipids, waxes suchas Carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax,microcrystalline wax, and paraffin wax; fat-containing mixtures such aschocolate; sugar in the form on an amorphous glass such as that used tomake hard candy forms, sugar in a supersaturated solution such as thatused to make fondant forms; low-moisture polymer solutions such asmixtures of gelatin and other hydrocolloids at water contents up toabout 30% such as those used to make “gummi” confection forms. In aparticularly preferred embodiment, the thermal setting material is awater-soluble polymer such as polyethylene glycol.

[0288] FIGS. 82-85 depict a preferred embodiment of the thermal settingmolding module 400. FIG. 82 is a side view, while FIGS. 83, 84 and 85A-Dare front views. The thermal setting molding module 400 generallyincludes a main rotor 402 as shown in FIGS. 3 and 82, on which aremounted a plurality of injection nozzle assemblies 404. Each injectionnozzle assembly 404 includes a housing 406, which is shown in FIGS.82-84, comprising a flow path 408 through which the starting materialmay flow. Mounted to each housing 406 are a plurality of nozzles 410.Although any number of nozzles may be employed in each injection nozzleassembly 404, preferably four are present. Mounted below each injectionnozzle assembly 404 is a thermal mold assembly 420 comprising aplurality of molding chambers 422 that correspond to the nozzles 410 ineach injection nozzle assembly 404.

[0289] A control valve 412, as shown in FIG. 83, is disposed within thehousing 406 for controlling the flow of starting material to each nozzle410. Disposed above the valve 412 may be a valve seat 414 and a gasket416 for sealing the valve 412 when it is in the closed position. Eachflow path 408 is connected to a reservoir 418 of starting material.Preferably, reservoir 418 is pressurized and heated with a suitable typeof heater (such an electronic resistance or induction type heat) to atemperature whereby the starting material will flow. In a preferredembodiment where the starting material comprises a polymer such aspolyethylene glycol, the temperature of the starting material ismaintained between about 50 and 80° C. in the reservoir.

[0290] Mounted below the nozzles is a plate 428 as shown in FIGS. 82 and85A-D. The plate 428 moves with nozzles 410 as shown in FIGS. 85A-D andas described below. Disposed within the plate 428 are cooling channels424 for coolant fluid to flow around the plate 428. The nozzles arepreferably heated, for example by a heat transfer fluid deliveredthrough channels 430 in housing 406. Coolant is provided to the moldassembly 420 and the plates 428. As described below, coolant flowsthrough channels 424 in order to cool and thereby harden the injectedstarting material. Plates 428 are coupled to the housing 406 by anysuitable means and in the preferred embodiment mechanical fasteners canbe used.

[0291] As shown in FIG. 82, shafts 442 are preferably slidably mountedwithin linear bearings 440. Preferably two shafts are present. Disposedbeneath the housing 406 and around a portion of the shafts 442 thatextend from the housing are springs 444. Shafts 442 extend beneath thesprings 444 as shown in FIGS. 85A-D into a block 446. As shown in FIGS.82 and 85A-D, and as described in more detail below, block 446 ismoveable in response to a cam follower 448, thereby moving closer tohousing 406 by compressing springs 444.

[0292] As shown in FIGS. 85A-D, block 446 is mounted about two shafts450 and moves up and down with the shafts 450. Shafts 450, as is shownin FIGS. 85A-D, are mounted within a bearing 452 that is coupled to camfollower 448, which rides in a cam track of the type known in the art.As cam follower 448 travels around the thermal setting molding module400 due to rotation of the rotor 402, cam follower 448 rides up and downin the cam track. As cam follower 448 moves up and down, housing 406,plate 428 and nozzles 410 also move. For instance, in FIG. 85A, camfollower 448 is at a high point. As rotor 402 rotates, cam follower 448rides down in the cam track and moves the mechanically linked bearing452 and block 446 in the downward direction to the position shown inFIG. 85B. Housing 406 and plate 428 also move. In this position, plate428 is disposed proximate to molding chambers 422, but nozzles 410 arestill disposed below the molding chambers 422.

[0293] Referring to FIG. 85C, continued rotation of rotor 402 moves camfollower 448 downward within the cam track. Plate 428, which is coupledto housing 406, cannot move downward because it is disposed against thethermal setting mold assembly 420. Consequently, block 446 exerts aforce on springs 444, compressing them. Block 446 pushes housing 406down into plate 428 and proximate the molding chambers 422. In thisposition, the starting material can be injected through the nozzles 410and into the molding chambers 422.

[0294] When housing 406 moves down as shown in FIG. 85C, control valve412 opens due to action of valve cam follower 417 in valve cam track419. Starting material is ported through control valve 412 and nozzles410 to fill mold chambers 422. Similarly, when cam follower 417 movesdown from the position of FIG. 85C to the position of FIG. 85D, controlvalve 412 closes to stop the flow of starting material. In a preferredembodiment of the invention, valve 412 is designed to provide a “suckback” action upon closing. As shown in FIGS. 83 and 84, the valve seat414 preferably has the geometry of a gradually tapering hole extendingfrom edge 414A to bottoming point 414B. As gasket 416, which ispreferably made of an elastomeric material, moves to a closed positionit enters the tapered valve seat 414 and creates a seal against the wallof the valve seat 414. As gasket 416 continues to move it acts like apiston forcing fluid in front of it and behind it to move upward asshown in FIG. 83. This in turn sucks back fluid from the tips of thenozzles 410, which assures that no starting material drools from oraccumulates on the tips of the nozzles. The volume of starting materialsucked back by movement of gasket 416 can be controlled and adjusted bythe depth to which the gasket penetrates into the valve seat.

[0295] As shown in FIG. 82, the thermal setting mold assemblies 420 aremounted to the rotor 402 by any suitable means. In a preferredembodiment, mechanical fasteners are used. When used in conjunction withother operating modules, rotor 402 may be attached to a common drivesystem with the other modules, so that they rotate in synchronicity,preferably by driven motor 50 as shown in FIG. 3.

[0296] A preferred embodiment of a thermal setting mold assembly 420 isshown in FIG. 86, which is a cross-section. Although one thermal settingmold assembly 420 is depicted, each of the thermal setting moldassemblies 420 are preferably the same.

[0297] Each thermal setting mold assembly 420 preferably comprises aplurality of molding chambers 422, which are empty volumetric spaceswithin the thermal setting mold inserts 423. Preferably, one thermalsetting mold insert 423 corresponds with each nozzle 410. In a preferredembodiment, there are four thermal setting mold inserts 423 aligned witheach of four nozzles 410, as best understood with reference to FIGS. 82and 85. Although the molding chambers 422 may be any shape and sizesuitable for molding, they are preferably generally cylindricallyshaped.

[0298] Disposed within each thermal setting mold insert 423 is a piston434. It will be appreciated from FIG. 86 that placement of piston 434within the each thermal setting mold insert 423 defines the volume ofthe mold cavity 422. By specifically sizing each mold cavity 422 andadjusting the position of piston 434, a desired volume and thereforeproper dosage of the starting material is obtained.

[0299] Preferably, the pistons 434 are adjustably controlled by theposition of cam follower 470 and associated cam track 468. Pistons 434are attached to piston attachment block 436 by suitable mechanical meansso that pistons 434 move with piston attachment block 436. Pistonattachment block 436 slides along the shafts 464 up and down.Preferably, there are two shafts 464 as shown in FIG. 86. Mounted topiston attachment block 436 is cam follower 470. One or more springs 466bias piston attachment block 436 and therefore pistons 434 into theinject position as viewed in FIG. 85C. As thermal setting mold assembly420 travels with rotor 402, cam follower 468 riding in its cam trackactuates pistons 434 into the eject position, which empties the moldingchamber in preparation for the next cycle (FIG. 85D).

[0300] Accordingly, during operation of the thermal setting moldingmodule 400, nozzles 410 move up during rotation of the thermal settingmolding module 400 and inject a starting material into molding chambers422. Next, starting material is hardened within the molding chambers 422into shaped pellets. Nozzles 410 are then retracted from the moldingchambers. All of this occurs as the molding chambers 422 and nozzles 410are rotating. After the starting material has hardened into shapedpellets, it is ejected from the molding chambers. See FIGS. 87 and 88.

[0301] When used with a transfer device 700 according to the invention,the transfer device 700 rotates between the molding chambers 422 andplate 428. The retainers 330 of the transfer device 700 receive theshaped pellets and transfers them to the another operating module, forexample a compression module 100. In the case of coupling a thermalsetting molding module 400 with a compression module 100 via a transferdevice 700, transfer device 700 inserts a shaped pellet into each diecavity 132 after the fill zone 102 but before the compression zone 106of the compression module. It will be appreciated that a linked thermalsetting molding module 400, transfer device 700 and compression module100 are synchronized so that a shaped pellet is placed into each diecavity 132. The process is a continuous one of forming shaped pellets,transferring the shaped pellets, and inserting the shaped pellets.

[0302] The thermal setting molding module has several unique features.One is the ability to mass produce shaped pellets relatively rapidly, inparticular molded dosage forms comprising polymers that are typicallysolids or solid-like between about 0 and about 35° C. The thermalsetting molding module accomplishes this is by heating the startingmaterial prior to injecting it into the molding chambers and thencooling the starting material after injection.

[0303] Another unique feature of the thermal setting molding module isthe adjustable volume of the molding chambers. Adjustability and tuningof volume and therefore weight is especially advantageous for theproduction of shaped pellets comprising high potency or highlyconcentrated drugs, which are dosed in small amounts. Another advantageof the thermal setting molding module is that it can employ liquids.Unlike a particulate solid, such as powders typically used to makedosage forms, the volume of a liquid is relatively invariable atconstant temperature. Density variations, which are troublesome inpowder compression, are therefore avoided with liquids. Very accurateweights, especially at very low weights (i.e. with starting materialscomprising high potency medicants) are achievable. Moreover, blenduniformity is also less assured with solid powders. Powder beds tend tosegregate based on differences in particle size, shape, and density.

[0304] Another advantage of the thermal setting molding module is thatit molds starting material while continuously rotating. This permits itsintegration with other continuously operating rotary devices, resultingin a continuous process. Conventional molding operations are typicallystationary and have one nozzle feeding multiple mold cavities. Runnersare often formed using in conventional equipment. By providing a nozzlefor each molding chamber, runners are eliminated. Preferably, onecontrol valve controls multiple nozzles. This simplifies the design ofthe thermal setting molding module, reducing costs. The thermal settingmolding module may, of course be designed to operate without rotation ofthe rotor, for example on an indexing basis whereby, a stationary groupof nozzles engages molding chambers on an indexing rotary turn table ora linear recalculating indexing belt or platen system. However, by usinga rotary system higher output rates can be achieved since products arecontinuously produced.

[0305] Specific embodiments of the present invention are illustrated byway of the following examples. This invention is not confined to thespecific limitations set forth in these examples, but rather to thescope of the appended claims. Unless otherwise stated, the percentagesand ratios given below are by weight.

[0306] In the examples, measurements were made as follows.

[0307] Coating thickness is measured using an environmental scanningelectron microscope, model XL 30 ESEM LaB6, Philips ElectronicInstruments Company, Mahwah, Wis. Six tablets from each sample aremeasured at 6 different locations on each tablet, as shown in FIG. 89.

[0308] Location 1: center of first major face, t_(c1)

[0309] Locations 2 and 3: edges (near punch land) of intersectionbetween first major face and side, t_(c2) and t_(c3)

[0310] Location 4: center of second major face, t_(c4)

[0311] Locations 5 and 6: edges (near punch land) of intersectionbetween second major face and side, t_(c5) and t_(c6)

[0312] Overall dosage form thickness and diameter are measured for 20dosage forms using a calibrated electronic digital caliper. Forthickness, the caliper is positioned across t as shown in FIG. 89. Fordiameter, the caliper is positioned at the midsections of the widestpoint of the dosage form sides shown in FIG. 89 as d.

EXAMPLE 1

[0313] A series of tablets having a molded gelatin coating thereon weremade according to the invention as follows.

[0314] Part A: Compressed Tablets

[0315] The following ingredients were mixed well in a plastic bag: 89.4parts acetaminophen USP (590 mg/tablet) and 8.0 parts of synthetic waxX-2068 T20 (53 mg/tablet). Next, 2.1 parts of sodium starch glycolate(EXPLOTAB) (13.9 mg/tablet) and 0.09 parts of silicon dioxide (0.6mg/tablet) were added to the bag, and mixed well. Then 0.36 parts ofmagnesium stearate NF (2.4 mg/tablet) were added to the bag, and theingredients were again mixed. The resulting dry blend was compressedinto tablets on a compression module according to the invention using{fraction (7/16)} inch extra deep concave tablet tooling. The resultingtablets had an average weight of 660 mg, thickness of 0.306 inches, andhardness of 3.2 kp.

[0316] The tablets from Part A were conveyed to a thermal cycle moldingmodule according to the invention via a transfer device also accordingto the present invention. The tablets were coated with red gelatin onone half thereof, and yellow gelatin on the other half thereof.

[0317] The red gelatin coating was made as follows. Purified water (450g), Opatint Red DD-1761 (4.4 g), and Opatint Yellow DD-2125 (1.8 g) weremixed at room temperature till uniform. 275 Bloom Pork Skin Gelatin (150g) and 250 Bloom Bone Gelatin (150 g) were added together in a separatecontainer. The dry gelatin granules were manually stirred to mix. Thepurified water/Opatint solution was added to the gelatin granules, andmixed for about 1 minute to completely wet the gelatin granules. Thegelatin slurry was placed in a water bath and heated to 55C to melt anddissolve the gelatin. The gelatin solution was held at 55C forapproximately 3 hours (holding times at this temperature can generallyrange between about 2 and about 16 hours). The solution was then mixeduntil uniform (about 5 to 15 minutes), and transferred to a jacketedfeed tank equipped with a propeller-type electric mixer. The gelatinsolution was maintained at 55C with continuous mixing during its use inthe thermal cycling molding module.

[0318] The yellow gelatin coating was made as follows. Purified water(450 g), and Opatint Yellow DD-2125 (6.2 g) were mixed at roomtemperature till uniform. 275 Bloom Pork Skin Gelatin (150 g) and 250Bloom Bone Gelatin (150 g) were added together in a separate container.The dry gelatin granules were stirred manually to mix. The purifiedwater/Opatint solution was added to the gelatin granules, and mixed forabout 1 minute to completely wet the gelatin granules. The gelatinslurry was placed in a water bath and heated to 55C to melt and dissolvethe gelatin. The gelatin solution was held at 55C for approximately 3hours (holding times at this temperature can generally range betweenabout 2 and about 16 hours). The solution was then mixed until uniform(about 5 to 15 minutes), and transferred to a jacketed feed tankequipped with a propeller-type electric mixer. The gelatin solution wasmaintained at 55C with continuous mixing during its use in the thermalcycling molding module.

EXAMPLE 2

[0319] Coating thickness was measured for samples of the followingtablets:

[0320] A. Extra Strength Tylenol GelTabs

[0321] B. Excedrine Migrane Geltabs

[0322] C. Tablets of produced according to Example 1.

[0323] The results are shown in Table 1 below. TABLE 1 A B C averagecoating thickness at major faces 145.17 microns 220.40 microns 195.37microns (locations 1, 4) for 6 tablets variability in coating thicknessat major faces 10.12%  5.01%  8.79% (locations 1, 4) for 6 tabletsaverage coating thickness (locations 1-6 for 6    85 microns 244.83microns 209.62 microns tablets) coating thickness variability (rsd forlocations 52.71% 12.64% 18.49% 1-6 for 6 tablets) average coatingthickness at edges  54.92 microns 257.05 microns 216.74 microns coatingthickness variability at edges (rsd for 19.80 11.88 20.56 locations 2,3, 5, 6 for 6 tablets) average difference in coating thickness  63.25%16.99% 15.93% between major face and edge (location 1- location2,location 4-location5) maximum difference in coating thickness    72% 33.4%  40.6% between major face and edge (location 1- location2,location 4-location5) minimum difference in coating thickness    54% 7.1%  4.1% between major face and edge (location 1- location2, location4-location5)

[0324] Thicknesses and diameters of 20 coated tablets from each of thethree samples were also measured. The results are summarized in Table 2below: TABLE 2 A B C average coated tablet thickness at  7.67 mm  6.55mm  7.99 mm major faces (across locations 1, 4) for 20 tabletsvariability in coated tablet thickness 0.407%  1.44% 0.292% at majorfaces (locations 1, 4) for 20 tablets average coated tablet diameter(across 11.46 mm 12.58 mm 11.74 mm locations 7, 8 for 20 tablets)variability in coated tablet diameter 0.183% 0.476% 0.275% (rsd acrosslocations 7, 8 for 20 tablets)

EXAMPLE 3

[0325] Compressed tablets were prepared according the method describedin Example 1. Press settings were held constant for a period of 7 hours,47 minutes. Tablets were sampled every 15 minutes. The resulting tabletshad the following properties:

[0326] Weight (mg) (average): 603.5

[0327] Weight (mg) (minimum): 582.2

[0328] Weight (mg) (maximum): 615.2

[0329] Weight (relative standard deviation (%)) 1.619

[0330] Thickness (inches) (average): 0.293

[0331] Thickness (inches) (minimum): 0.29

[0332] Thickness (inches) (maximum): 0.30

[0333] Thickness (relative standard deviation (%)) 1.499

[0334] Hardness (kp) (average): 1.713

[0335] Hardness (kp) (minimum): 1.12

[0336] Hardness (kp) (maximum): 3.16

[0337] Hardness (relative standard deviation (%)) 21.8

EXAMPLE 4

[0338] A flowable material suitable for coating a compressed dosage formwas made as follows. The flowable material may be applied using athermal cycle molding module according to the invention. Material % w/wPEG 1450 (part 1) 30.0 PEG 1450 (part 2)   30-50% Polyethylene Oxide300,000 15.0-25% Glycerin   0-10% Red color solution* (3% w/w) 5Propylene Glycol (4.85) Red #40 dye (0.15)

[0339] Polyethylene glycol (PEG) 1450 (part 1) and polyethylene oxide(PEO) 300,000 were shaken in a plastic bag until powders were mixedevenly. The (5 qt) bowl of a planetary mixer (Hobart Corp., Dayton,Ohio) was heated to 80C by circulating hot water. PEG 1450 (part 2) waspoured into the bowl and melted to form a liquid. The color solution,and optionally, the glycerin were added while mixing at low speed. ThePEG/PEO powder mixture was added and the mixture mixed for 15 minutes.The resulting mixture was allowed to stand in the Hobart bowl for 2hours while maintaining the temperature at 80C. Cast films(approximately 0.8 mm thick) were prepared using a stainless steel mold(2″×5″×0.8 mm). The solution was transferred to a jacketed beaker (80C)and de-aerated by vacuum for 6 hours. A second film was prepared usingthe same mold.

[0340] Increasing PEO from 15 to 25% (with corresponding decrease in PEGfrom 85 to 75%) increased yield stress (maximum force per unit areawhich can be applied before the film will deform permanently), andincreased strain (% film elongation at break point).

[0341] Decreasing glycerin from 10% to 2% increased Tensile Strength(force per unit area required to break the film). Deaerating theglycerin-containing films prior to casting generally decreased tensilestrength.

EXAMPLE 5

[0342] Another flowable material suitable for coating a compresseddosage form was made as follows. The flowable material may be appliedusing a thermal cycle molding module according to the invention.Material % w/w PEG 1450 granular 70-75% Polyethylene Oxide 600,000 15%White beeswax  5-10% Red color solution* (3% w/w) 5 Propylene Glycol(4.85) Red #40 dye (0.15)

[0343] The (5 qt) bowl of a planetary mixer (Hobart Corp., Dayton, Ohio)was heated to 80C by circulating hot water. PEG 3350 granular was pouredinto the bowl and melted to form a liquid. The white beeswax, colorsolution, and polyethylene oxide were added while mixing at low speed.The resulting mixture was mixed for a total of 12 minutes, then allowedto stand in the Hobart bowl for 2 hours while maintaining thetemperature at 80C. Cast films were prepared using a glass slide. Thesolution was transferred to a jacketed beaker (80C) and de-aerated byvacuum for 6 hours. A second film was prepared using the same mold.

[0344] The white beeswax formula had increased tensile strength comparedto the glycerin formulas.

[0345] Examples 4 and 5 illustrate suitable formulations for theflowable material. Advantageously, these formulations are solvent(including water) free. This eliminates the need to evaporate solventfrom coatings made from such formulations, shortening and simplifyingdrying. Accordingly, in one embodiment of the invention, the flowablematerial is substantially solvent-free, that is contains less than about1 weight percent, preferably no, solvent.

What is claimed is:
 1. A method of forming compressed dosage forms,comprising: a) placing a supply of powder in flow communication with adie, said die comprising a die cavity therein in flow communication witha filter; b) applying suction to said die cavity so as to cause powderto flow into said die cavity, said suction being applied to said diecavity through said filter; c) isolating said filter from said powder insaid die cavity; and d) compressing said powder in said die cavity so asto form a compressed dosage form while said filter is isolatedtherefrom.
 2. The method according to claim 1, wherein the filter is ascreen having a mesh size larger than the average particle size of thepowder.
 3. The method according to claim 1, wherein said filtercommunicates with said die cavity through a port in said die cavity, andwherein said isolating step (c) comprises moving a first punch throughsaid die cavity to cover said port, and wherein said compressing step(d) comprises moving a second punch through said die cavity toward saidfirst punch.
 4. The method according to claim 1, wherein a portion ofsaid powder flowing through said cavity is trapped in said filter, saidmethod further comprising the steps of: (e) purging said trapped powderfrom said filter after compression step (d); and (f) directing saidpurged powder back to said die cavity, whereby said trapped powder isrecycled.
 5. The method according to claim 4, wherein said directingstep (f) comprises (i) directing said purged powder to said powdersupply, and (ii) directing said purged powder from said powder supply tosaid die cavity.
 6. The method according to claim 4, wherein saiddirecting step (f) comprises directing said purged powder directly backto said die cavity.
 7. The method according to claim 1, wherein saidpowder has a minimum orifice diameter of flowability greater than about30 mm as measured by the Flodex test.
 8. The method according to claim7, wherein the relative standard deviation in weight of said compresseddosage forms is less than about 2%.
 9. The method according to claim 7,wherein the relative standard deviation in weight of said compresseddosage forms is less than about 1%.
 10. The method according to claim 1,wherein said powder comprises at least 85 percent by weight of medicantand has an average particle size of about 50 to about 300 microns. 11.The method according to claim 10, wherein the relative standarddeviation in weight of said compressed dosage forms is less than about1%.
 12. The method according to claim 1, wherein said powder is made bydry blending.
 13. An apparatus for forming compressed dosage forms,comprising: a) a suction source; b) a die cavity having (i) a first portfor placing said die cavity in flow communication with said suctionsource, whereby said suction source applies suction to said die cavity,and (ii) a second port for placing said die cavity in flow communicationwith a supply of powder, whereby said suction source assists said powderin flowing into said die cavity; (c) a filter disposed between saidsuction source and said second port, whereby suction is applied to saiddie cavity through said filter; and (d) a punch for compressing saidpowder in said die cavity so as to form said compressed dosage forms.14. The apparatus according to claim 13, wherein said punch is mountedfor motion between first and second positions, said first positiondisposed below said first and second ports, and said second positiondisposed between said first and second ports, whereby said punchisolates said first port from said die cavity when in said secondposition.
 15. The apparatus according to claim 13, wherein a portion ofsaid powder that flows through said cavity is trapped in said filter,said apparatus further comprising: e) a source of pressurized fluid; f)a conduit for placing said pressurized fluid in flow communication withsaid filter so as to purge said trapped powder from said filter.
 16. Theapparatus according to claim 15, further comprising means for recoveringpowder trapped by said filter and means for recycling said recoveredpowder back to said die cavity.
 17. The apparatus of claim 13, which iscapable of compressing said powder with a force of at least 20 kN. 18.The apparatus of claim 13, wherein said filter is disposed within saiddie cavity.
 19. The apparatus of claim 13, wherein said filter isdisposed proximal to said die cavity.
 20. The apparatus according toclaim 13, wherein said die table further comprises a plurality ofopenings on its outer periphery, a plurality of channels connecting saidopenings with said die cavities, and a shoe block contacting a portionof the outer periphery of said die table and aligned with said openings,such that said shoe block covers said openings upon rotation of said dietable past said shoe block.
 21. An apparatus for forming compresseddosage forms from a powder, comprising a) a die table having a pluralityof die cavities therein, said die cavities being arranged in multiple,concentric rows around the perimeter of said die table; b) punchesaligned with and insertable into said die cavities for compressing saidpowder into compressed dosage forms in each of said die cavities; and c)rollers aligned with each of said concentric rows of die cavities forpressing said punches into said die cavities, each roller being sizedsuch that the dwell time under compression of all of said punches isequal.
 22. The apparatus according to claim 21, wherein said rollers aremounted on at least one compression frame capable of deflecting underthe force of compression, such that upon deflection of said compressionframe, said rollers are radially displaced in a direction parallel totheir original position.
 23. The apparatus according to claim 22,wherein said frame has a C-shape.
 24. The apparatus of claim 22, whereinsaid compression frame comprises a throat and two arms, wherein saidarms form an oblique angle with respect to the axial axis of saidrollers.
 25. The apparatus of claim 22, wherein said compression frameis capable of pivoting about an axis to move away from the compressionmodule.
 26. The apparatus according to claim 22, wherein the compressionframe is capable of withstanding a force of up to about 200 kN.
 27. Arotary compression module for forming compressed dosage forms from apowder, comprising a) a single fill zone; b) a single compression zone;c) a single ejection zone; d) a circular die table having a plurality ofdie cavities therein; and e) punches aligned with and insertable intosaid die cavities for compressing said powder into compressed dosageforms in each of said die cavities; wherein the number of die cavitiesin said module is greater than the maximum number of die cavities thatcan be arranged in a single circle around the circumference of a similardie table having the same diameter as the circular die table, andwherein the dwell time under compression of all of said punches isequal.
 28. Compressed dosage forms made from a powder having a minimumorifice diameter of flowablility greater than about 10 mm as measured bythe Flowdex test, the relative standard deviation in weight of saidcompressed dosage forms being less than about 2%, and made using alinear velocity at the die of at least about 230 cm/sec.
 29. Compresseddosage forms made from a powder having a minimum orifice diameter offlowablility greater than about 15 mm as measured by the Flowdex test,the relative standard deviation in weight of said compressed dosageforms being less than about 2%, and made using a linear velocity at thedie of at least about 230 cm/sec.
 30. Compressed dosage forms made froma powder having a minimum orifice diameter of flowablility greater thanabout 25 mm as measured by the Flowdex test, the relative standarddeviation in weight of said compressed dosage forms being less thanabout 2%, and made using a linear at the die velocity of at least about230 cm/sec.
 31. Compressed dosage forms made from a powder having aminimum orifice diameter of flowablility greater than about 10 mm asmeasured by the Flowdex test, the relative standard deviation in weightof said compressed dosage forms being less than about 1%, and made usinga linear velocity at the die of at least about 230 cm/sec. 32.Compressed dosage forms made from a powder having a minimum orificediameter of flowablility greater than about 10 mm as measured by theFlowdex test, the relative standard deviation in weight of saidcompressed dosage forms being less than about 2%, and made using alinear velocity at the die of at least about 115 cm/sec.
 33. Compresseddosage forms made from a powder having an average particle size of about50 to about 150 microns and containing at least about 85 percent byweight of a medicant, the relative standard deviation in weight of saidcompressed dosage forms being less than about 1%.
 34. Compressed dosageforms containing at least about 85 percent by weight of a medicant andbeing substantially free of water soluble polymeric binders, therelative standard deviation in weight of said compressed dosage formsbeing less than about 2%.
 35. Compressed dosage forms containing atleast about 85 percent by weight of a medicant and being substantiallyfree of water soluble polymeric binders, the relative standard deviationin weight of said compressed dosage forms being less than about 1%. 36.Compressed dosage forms containing at least about 85 percent by weightof a medicant selected from the group consisting of acetaminophen,ibuprofen, flurbiprofen, ketoprofen, naproxen, diclofenac, aspirin,pseudoephedrine, phenylpropanolamine, chlorpheniramine maleate,dextromethorphan, diphenhydramine, famotidine, loperamide, ranitidine,cimetidine, astemizole, terfenadine, fexofenadine, loratadine,cetirizine, antacids, mixtures thereof and pharmaceutically acceptablesalts thereof, and being substantially free of water soluble polymericbinders, the relative standard deviation in weight of said compresseddosage forms being less than about 2%.
 37. Compressed dosage formscontaining at least about 85 percent by weight of a medicant and beingsubstantially free of hydrated polymers, the relative standard deviationin weight of said compressed dosage forms being less than about 2%. 38.Compressed dosage forms containing at least about 85 percent by weightof a medicant and being substantially free of hydrated polymers, therelative standard deviation in weight of said compressed dosage formsbeing less than about 1%.
 39. Compressed dosage forms containing atleast about 85 percent by weight of a medicant selected from the groupconsisting of acetaminophen, ibuprofen, flurbiprofen, ketoprofen,naproxen, diclofenac, aspirin, pseudoephedrine, phenylpropanolamine,chlorpheniramine maleate, dextromethorphan, diphenhydramine, famotidine,loperamide, ranitidine, cimetidine, astemizole, terfenadine,fexofenadine, loratadine, cetirizine, antacids, mixtures thereof andpharmaceutically acceptable salts thereof, and being substantially freeof hydrated polymers, the relative standard deviation in weight of saidcompressed dosage forms being less than about 2%.